{"gene":"HNRNPK","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2001,"finding":"MAPK/ERK phosphorylates hnRNPK at serines 284 and 353 both in vitro and in vivo; this phosphorylation drives cytoplasmic accumulation of hnRNPK, which is required for its ability to silence mRNA translation of transcripts containing a differentiation-control element (DICE) in the 3' UTR. Mutation of ERK phosphoacceptor sites abolishes cytoplasmic accumulation and translational repression.","method":"In vitro kinase assay, site-directed mutagenesis, pharmacological ERK inhibition, subcellular fractionation, constitutively active MEK1 overexpression","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro phosphorylation assay with mutagenesis, multiple orthogonal approaches (mutant rescue, pharmacological inhibition, fractionation), single rigorous study","pmids":["11231586"],"is_preprint":false},{"year":2017,"finding":"hnRNPK is the principal binding factor for the Xist RNA Polycomb Interaction Domain (XR-PID, encompassing the B-repeat element) and is required to recruit PCGF3/5-PRC1 to the inactive X chromosome. Deletion of XR-PID abolishes Polycomb recruitment, Xist-mediated gene silencing, and chromatin inaccessibility; synthetic tethering of hnRNPK to Xist RNA lacking XR-PID restores Polycomb recruitment.","method":"RNA deletion mutagenesis, hnRNPK knockdown, synthetic tethering rescue, chromatin accessibility assays, RNA-protein interaction studies","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal loss-of-function and rescue experiments establishing pathway position, replicated across approaches","pmids":["29220657"],"is_preprint":false},{"year":2012,"finding":"UV-induced SUMOylation of hnRNPK by the E3 ligase PIAS3 (in an ATR-dependent manner) prevents HDM2-mediated ubiquitination and proteasomal degradation of hnRNPK, stabilizing it and increasing its affinity for p53 over HDM2, thereby enabling hnRNPK to act as a transcriptional co-activator of p53 for p21-mediated cell-cycle arrest. Later, SENP2 removes SUMO from hnRNPK, destabilizing it and releasing the cell-cycle arrest.","method":"SUMOylation-defective mutant analysis, purified SUMOylated hnRNPK binding assays, siRNA knockdown of PIAS3/SENP2, co-immunoprecipitation","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — biochemical reconstitution with purified proteins, mutagenesis, and multiple orthogonal methods in a single rigorous study","pmids":["23092970"],"is_preprint":false},{"year":2014,"finding":"Arginine methylation of hnRNPK at Arg296 and Arg299 inhibits nearby Ser302 phosphorylation mediated by the pro-apoptotic kinase PKCδ, thereby negatively regulating apoptosis following DNA damage. Cells expressing methylation-defective hnRNPK mutants show increased apoptosis through both intrinsic and extrinsic pathways in a p53-independent manner.","method":"Site-directed mutagenesis (Arg296/299), in vitro kinase assays, engineered U2OS cell lines, apoptosis assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — mutagenesis combined with multiple functional readouts and rescue experiments in a single rigorous study","pmids":["25104022"],"is_preprint":false},{"year":2011,"finding":"During oligodendrocyte differentiation and myelination, α6β1-integrin activation interacts with hnRNP-K, which binds MBP mRNA and translocates from the nucleus to the myelin sheath, reversing the inhibitory effect of the MBP mRNA 3'UTR on translation; knockdown of hnRNP-K inhibits MBP protein synthesis during myelination.","method":"Co-immunoprecipitation, siRNA knockdown, subcellular fractionation/live imaging, in vitro translation assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, direct localization experiment with functional consequence, KD with specific phenotypic readout, multiple orthogonal methods","pmids":["21357748"],"is_preprint":false},{"year":2005,"finding":"BCR/ABL activates hnRNPK expression and activity via the MAPK/ERK1/2 pathway; elevated hnRNPK enhances IRES-dependent MYC mRNA translation, contributing to leukemogenic proliferation and clonogenic potential. Interference with hnRNPK translation-regulatory activity (but not transcription-regulatory activity) impairs BCR/ABL-driven leukemogenesis.","method":"siRNA knockdown, dominant-negative constructs distinguishing translation vs. transcription functions, in vivo leukemogenesis assays, IRES reporter assays","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Moderate — specific domain dissection distinguishing translation from transcription function, in vitro and in vivo validation, multiple orthogonal methods","pmids":["16293596"],"is_preprint":false},{"year":2006,"finding":"hnRNPK directly interacts with N-WASP via the WH1 domain of N-WASP and the KI domain of hnRNPK; co-expression of hnRNPK with N-WASP reverses N-WASP-stimulated cell spreading and reduces filopodia formation, identifying hnRNPK as a negative regulator of N-WASP at the spreading initiation center.","method":"Co-immunoprecipitation, domain mapping, co-localization imaging, cell spreading and filopodia assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct interaction mapped to specific domains, multiple functional readouts (spreading, filopodia), co-localization confirmed","pmids":["16574661"],"is_preprint":false},{"year":2011,"finding":"Aurora-A kinase phosphorylates hnRNPK at serine 379; this phosphorylation disrupts the interaction of hnRNPK with p53 without affecting hnRNPK post-transcriptional activity or cellular localization, providing a mechanism by which Aurora-A reduces p53 transcriptional activity during DNA damage.","method":"In vitro kinase assay, co-immunoprecipitation, site-directed mutagenesis (S379)","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — reciprocal Co-IP and in vitro kinase assay with mutagenesis, single lab, single paper","pmids":["21821029"],"is_preprint":false},{"year":2015,"finding":"During RANKL-induced osteoclast differentiation, PI3K/Akt-mediated Ser9 phosphorylation of GSK3β triggers ERK-dependent nuclear-to-cytoplasmic translocation of hnRNPK; cytoplasmic hnRNPK interacts with GSK3β and regulates NF-κB activation, NFATc1 expression, and tubulin acetylation, all critical for osteoclast differentiation. hnRNPK is also localized in the actin belt of mature osteoclasts.","method":"Co-immunoprecipitation, subcellular fractionation, siRNA knockdown, immunofluorescence localization, osteoclast differentiation assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, localization with functional consequence, knockdown with specific phenotypic readout, single lab with multiple orthogonal methods","pmids":["26638989"],"is_preprint":false},{"year":2019,"finding":"HNRNPK is necessary for DDX6-mediated binding and degradation of a subset of mRNAs encoding differentiation-promoting transcription factors (GRHL3, KLF4, ZNF750) in epidermal progenitor cells, preventing premature differentiation. HNRNPK is also required for RNA Polymerase II binding to proliferation/self-renewal genes (MYC, CYR61, FGFR1, EGFR, cyclins) to sustain progenitor proliferative capacity.","method":"HNRNPK siRNA knockdown, RNA-seq, ChIP for RNA Pol II, mRNA stability assays, RIP for DDX6","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (ChIP, RIP, RNA-seq, KD), defines two distinct mechanistic roles, single lab","pmids":["31519929"],"is_preprint":false},{"year":2015,"finding":"HNRNPK interacts directly with HCV RNA (but not Dengue virus RNA), and mutations that impair this RNA interaction also reduce HNRNPK's ability to suppress HCV particle production. In HCV-infected cells, HNRNPK is redistributed to sites adjacent to lipid droplets, co-localizing with core protein and HCV plus-strand RNA. The mechanism involves limiting viral RNA availability for incorporation into virions.","method":"siRNA knockdown, domain mapping rescue experiments, RNA-protein interaction assays, co-localization imaging, virion production assays","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Moderate — knockdown-rescue domain mapping, RNA binding-function correlation, co-localization, multiple orthogonal methods in single rigorous study","pmids":["25569684"],"is_preprint":false},{"year":2013,"finding":"hnRNPK, together with Tcl1, promotes G6PD pre-mRNA splicing and increases G6PD protein expression; PTEN forms a complex with hnRNPK and inhibits this G6PD pre-mRNA splicing, thereby antagonizing the Tcl1/hnRNPK-mediated enhancement of the pentose phosphate pathway in hepatocellular carcinoma.","method":"Co-immunoprecipitation, mass spectrometry, splicing assays, siRNA knockdown, biochemical complex analysis","journal":"Gut","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, mass spectrometry, splicing assays with knockdown, single lab","pmids":["24352616"],"is_preprint":false},{"year":2021,"finding":"hnRNPK acts downstream of TNFα-TNFR2 signaling to directly interact with and stabilize YAP on target gene promoters genome-wide, co-regulating YAP target gene expression in hepatic progenitor cells. TNFR1 does not mediate this effect.","method":"Co-immunoprecipitation, ChIP-seq, siRNA knockdown, single-cell RNA sequencing","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide ChIP-seq, Co-IP, and KD with specific phenotypic readout, single lab","pmids":["33619115"],"is_preprint":false},{"year":2017,"finding":"hnRNPK regulates alternative splicing of MRPL33 pre-mRNA to promote inclusion of exon 3, producing the long isoform MRPL33-L; knockdown of hnRNPK phenocopies MRPL33-L depletion (impaired proliferation, increased apoptosis, mitochondrial dysfunction), and overexpression of MRPL33-L can rescue hnRNPK-depleted cells, placing hnRNPK upstream of MRPL33-L in a cancer-relevant splicing pathway.","method":"siRNA knockdown, overexpression rescue, RT-PCR splicing assay, mitochondrial functional assays, xenograft model","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — epistasis established by rescue, multiple functional readouts both in vitro and in vivo, single lab with multiple orthogonal methods","pmids":["28869607"],"is_preprint":false},{"year":2002,"finding":"hnRNP-K and Purα act together to repress transcriptional activity of the CD43 gene promoter during K562 cell activation by binding single-stranded DNA sequences in the promoter.","method":"Transcriptional reporter assays, electrophoretic mobility shift assays (EMSA), co-immunoprecipitation","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMSA plus reporter assays, protein-DNA binding and co-IP, single lab","pmids":["12411317"],"is_preprint":false},{"year":2019,"finding":"In pancreatic β cells under glucolipotoxic metabolic stress, MEK/ERK signaling phosphorylates hnRNPK, which then binds the 3'UTR poly-C motif of JUND mRNA and recruits the RNA helicase DDX3X as a binding partner to promote efficient JUND mRNA translation. Loss of hnRNPK blocks post-transcriptional JUND upregulation, and hnRNPK loss reduces DDX3X association with translation machinery.","method":"RNA immunoprecipitation, co-immunoprecipitation, Phos-tag analysis, TRAP-qPCR, CRISPR-Cas9 KO, lentiviral delivery","journal":"Molecular metabolism","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (RIP, Co-IP, Phos-tag, TRAP), functional validation in primary islets and cell line, single lab","pmids":["31178390"],"is_preprint":false},{"year":2013,"finding":"hnRNP-K promotes tumor metastasis by regulating extracellular matrix, cell motility, and angiogenesis gene-expression pathways (including Cck, Mmp-3, Ptgs2, and Ctgf), as established in hnRNP-K-overexpressing and -underexpressing cell lines with in vitro and in vivo metastasis assays.","method":"Stable hnRNPK overexpression/knockdown cell lines, cDNA microarray, pathway analysis, in vivo metastasis assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with in vivo validation, pathway-level mechanistic dissection, single lab","pmids":["23564449"],"is_preprint":false},{"year":2017,"finding":"hnRNPK regulates PLK1 expression post-transcriptionally through KH1- and KH2-dependent interactions with cytosine-rich sequences in the 3'UTR of PLK1 mRNA, and competes with miR-149-3p and miR-193b-5p for this shared C-rich motif to influence PLK1 mRNA stability and Ago2 association.","method":"siRNA knockdown, overexpression, Ago2 immunoprecipitation, 3'UTR deletion mutants, luciferase reporter assays","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain mapping (KH1/KH2), competition with miRNAs at defined motif, Ago2-IP, single lab","pmids":["28708135"],"is_preprint":false},{"year":2016,"finding":"hnRNPK translocated from nucleus to cytoplasm (via MAPK/ERK) binds to and inhibits Ser9 phosphorylation of GSK3β by PKC, thereby maintaining GSK3β in an active state that stabilizes c-FLIP protein and contributes to TRAIL resistance in H1299 lung adenocarcinoma cells.","method":"Subcellular fractionation, co-immunoprecipitation, co-localization imaging, GSK3β phosphorylation assays, c-FLIP stability assays, tissue microarray","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, localization with functional consequence, multiple signaling readouts, single lab","pmids":["26972480"],"is_preprint":false},{"year":2005,"finding":"Cytoplasmic hnRNP-K forms a multi-protein complex with calponin and ERK1/2 in smooth muscle cells; nuclear-to-cytoplasmic translocation of hnRNP-K is cell cycle-dependent, with cytoplasmic hnRNP-K appearing at later cell cycle stages, partly by translocation from the nucleus.","method":"Subcellular fractionation across cell cycle, cycloheximide chase, co-immunoprecipitation","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization experiment with functional context, Co-IP establishing complex, single lab","pmids":["15962305"],"is_preprint":false},{"year":2008,"finding":"African swine fever virus protein p30 interacts with hnRNP-K through the KH1 and KH2 domains (residues 35–197) of hnRNP-K; this interaction occurs mainly in the nucleus, alters hnRNP-K subcellular distribution, and decreases nascent RNA synthesis in infected cells.","method":"Yeast two-hybrid, co-localization imaging, domain mapping, 5-fluorouridine incorporation assay","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — yeast two-hybrid with domain mapping, functional readout (RNA synthesis), co-localization, single lab","pmids":["18775702"],"is_preprint":false},{"year":2013,"finding":"hnRNP-K binds the distal polyadenylation element of SERT mRNA; Src-family kinase-mediated tyrosine phosphorylation of hnRNPK (induced by trophic factor S100β) is associated with increased SERT protein expression, suggesting hnRNPK holds SERT mRNA in a translationally repressed state that is relieved upon tyrosine phosphorylation.","method":"RNA-protein binding assays, genetic manipulation of hnRNPK, pharmacological Src inhibition, western blot for SERT protein","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct RNA binding, functional genetics, phosphorylation-function correlation, single lab","pmids":["23798440"],"is_preprint":false},{"year":2014,"finding":"Angiopoietin-1 stimulates Src-family kinase recruitment to hnRNP-K and tyrosine phosphorylation of hnRNP-K (requiring Tyr458); this phosphorylation prevents hnRNP-K from binding UCP2 mRNA, releasing it for translation and increasing UCP2 protein expression in endothelial cells without changing total UCP2 mRNA levels.","method":"In vitro Src phosphorylation of purified hnRNP-K, RIP, site-directed mutagenesis (Y458), co-immunoprecipitation, western blot","journal":"Cellular signalling","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro reconstitution with purified proteins, mutagenesis at specific residue, RIP and functional protein expression readout, single lab","pmids":["24642125"],"is_preprint":false},{"year":2021,"finding":"CAV1 (non-caveolar, in the absence of CAVIN1) drives localization of hnRNPK to multi-vesicular bodies (MVBs), recruiting AsUGnA motif-containing miRNAs for selective loading into exosomes; knockdown of hnRNPK abolishes PC3 extracellular vesicle-induced osteoclastogenesis, establishing hnRNPK as a miRNA sorting factor for exosomal release.","method":"hnRNPK knockdown, co-localization imaging, cholesterol depletion, miRNA pulldown, osteoclastogenesis assay","journal":"Clinical and translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — localization with functional consequence, knockdown with specific phenotypic readout, multiple orthogonal approaches, single lab","pmids":["33931969"],"is_preprint":false},{"year":2021,"finding":"hnRNPK facilitates cytoplasmic interaction with and stabilization of β-catenin by inhibiting its proteasome-mediated degradation; lncRNA pancEts-1 promotes this interaction by binding hnRNPK and facilitating its physical interaction with β-catenin.","method":"Co-immunoprecipitation, siRNA knockdown, proteasome inhibitor assays, lncRNA pulldown","journal":"Cancer research (reported in PMID:29311158)","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP of hnRNPK-β-catenin complex, proteasome assay, single lab","pmids":["29311158"],"is_preprint":false},{"year":2022,"finding":"SCFFbxo4 E3 ubiquitin ligase restricts hnRNPK pro-oncogenic activity via K63-linked polyubiquitylation, limiting hnRNPK's ability to bind target mRNAs. Loss of SCFFbxo4 leads to hnRNPK-dependent increase in c-Myc mRNA translation, enhanced cell invasion, and tumor metastasis.","method":"Co-immunoprecipitation, ubiquitylation assays (K63 linkage), polysome profiling, siRNA/genetic KO, invasion assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — biochemical ubiquitylation assay with linkage specificity, functional rescue experiments, multiple orthogonal methods, single lab","pmids":["36329064"],"is_preprint":false},{"year":2019,"finding":"hnRNPK activates transcription of the SRSF1 splicing regulator by binding to a motif upstream of the start codon (−65 to −77 site), thereby increasing expression of the oncogenic CD44E isoform (CD44v8-v10) in gastric cancer cells.","method":"ChIP assay, dual luciferase reporter assay, siRNA knockdown, RT-PCR splicing analysis","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and reporter assay define binding site, KD with splicing readout, single lab","pmids":["31857793"],"is_preprint":false},{"year":2015,"finding":"hnRNP-K interacts with Ehrlichia entry-triggering protein EtpE-C via CD147 and cytoplasmic hnRNP-K; hnRNP-K activates N-WASP-dependent actin polymerization to drive bacterial entry. Functional ablation of cytoplasmic hnRNP-K by intracellular nanobody markedly attenuated Ehrlichia entry and infection.","method":"Affinity pulldown, far-Western blot, co-immunoprecipitation, shRNA knockdown, intracellular nanobody, in vitro actin polymerization assay, time-lapse imaging","journal":"mBio","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal validation methods including in vitro actin polymerization reconstitution, specific domain ablation, multiple independent validations","pmids":["26530384"],"is_preprint":false},{"year":2009,"finding":"TCR-activated ERK phosphorylates hnRNP-K in the nucleus of T cells; hnRNP-K knockdown abrogates IL-2 production and causes increased proteolysis of Vav1 (a binding target of hnRNP-K), suggesting hnRNPK protects Vav1 from activation-induced degradation and is required for T cell activation.","method":"Proteomic analysis of TCR-activated nuclear proteins, siRNA knockdown, western blot for Vav1","journal":"International immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with specific functional readout (IL-2, Vav1 proteolysis), nuclear localization demonstrated, single lab","pmids":["19880579"],"is_preprint":false},{"year":2017,"finding":"hnRNPK binds to the miR-223 promoter, and siRNA knockdown of hnRNPK reduces miR-223 levels in pancreatic cancer cells. FBXW7 interacts with hnRNPK and promotes its degradation via GSK3-mediated phosphorylation at threonine 1695, forming a feedback cascade.","method":"ChIP, siRNA knockdown, co-immunoprecipitation, GSK3 phosphorylation assay","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP for promoter binding, Co-IP for protein interaction, phosphorylation assay, single lab","pmids":["28423622"],"is_preprint":false},{"year":2021,"finding":"Circ-GALNT16 binds the KH3 domain of hnRNPK and promotes its SUMOylation, thereby enhancing formation of an hnRNPK-p53 transcriptional complex; SUMOylation of hnRNPK inhibited by SENP2 reduces sequence-specific DNA binding of the hnRNPK-p53 complex, regulating Serpine1 transcription.","method":"RNA pulldown, RIP, co-immunoprecipitation, ChIP, RNA sequencing, domain mapping (KH3)","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-specific RNA-protein interaction, SUMOylation-function link, ChIP, single lab","pmids":["34452628"],"is_preprint":false},{"year":2022,"finding":"hnRNPK alleviates RNA toxicity in C9orf72 ALS by counteracting DNA damage; HNRNPK subcellular localization (cytoplasmic mislocalization observed in patient cells) and RNA recognition are required for this function. hnRNPK transcriptionally controls RRM2 (ribonucleotide reductase regulatory subunit M2), and increasing either hnRNPK or RRM2 expression mitigates DNA damage in a C9orf72 RNA toxicity zebrafish model.","method":"Zebrafish overexpression model, patient fibroblasts/iPSC-derived motor neurons, post-mortem tissue, DNA damage assays, subcellular fractionation","journal":"Acta neuropathologica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo model with rescue, patient tissue validation, subcellular localization with functional consequence, single lab","pmids":["35895140"],"is_preprint":false},{"year":2024,"finding":"The KH1 and KH2 domains of hnRNPK bind and promote degradation of WWC1 mRNA; hnRNPK deletion increases WWC1 expression, activating Hippo signaling and aggravating osteoarthritis. Intra-articular AAV5-hnRNPK protects against OA, and WWC1 RNAi rescues cartilage degeneration caused by hnRNPK deletion.","method":"Conditional KO mice, AAV rescue, RIP/domain mapping, in vivo OA models, mRNA stability assays","journal":"Molecular therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-specific KH1/KH2 mechanism, in vivo genetic epistasis by rescue, single lab","pmids":["38414246"],"is_preprint":false},{"year":2022,"finding":"hnRNPK binds Hif1a mRNA and promotes its degradation via its KH domains; hnRNPK deletion in chondrocytes increases Hif1α protein, leading to exorbitant glycolysis and impaired chondrocyte survival and differentiation, causing dwarfism.","method":"Conditional chondrocyte KO mice, RIP, mRNA stability assay, metabolic assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP establishes direct mRNA binding, KO with in vivo phenotypic readout, single lab","pmids":["36127325"],"is_preprint":false},{"year":2021,"finding":"SGLT2 interacts with hnRNPK and promotes hnRNPK nuclear translocation, thereby enhancing hnRNPK-induced YAP1 transcription, activating Hippo signaling in pancreatic cancer cells.","method":"Liquid chromatography-mass spectrometry, co-immunoprecipitation, subcellular fractionation, siRNA knockdown, transcription reporter assay","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP validated by LC-MS, subcellular localization with functional consequence, single lab","pmids":["34314754"],"is_preprint":false},{"year":2019,"finding":"O-GlcNAcylation of hnRNP-K is required for its nuclear translocation; suppression of O-GlcNAcylation retains hnRNP-K in the cytoplasm in cholangiocarcinoma cells, reducing their migratory capabilities.","method":"Click chemistry enzymatic labeling, LC-MS/MS proteomics, anti-OGP/anti-hnRNPK immunoprecipitation, sWGA pulldown, siRNA knockdown, subcellular fractionation","journal":"Molecular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mass spectrometry identification of modification, functional localization-migration link, multiple validation methods, single lab","pmids":["30444036"],"is_preprint":false},{"year":2014,"finding":"SET protein directly interacts with hnRNPK and increases hnRNPK's binding to nucleic acids; SET accumulation promotes hnRNPK nuclear localization and enhances Bcl-xS repression.","method":"Co-immunoprecipitation, overexpression/knockdown, nucleic acid binding assays, subcellular fractionation","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP/pulldown, single lab, limited mechanistic follow-up","pmids":["24508256"],"is_preprint":false},{"year":2021,"finding":"Arginine methylation of hnRNPK inhibits the DDX3-hnRNPK interaction; DDX3 C-terminus preferentially binds unmethylated hnRNPK and promotes apoptosis in osteosarcoma cells. A small molecule docking at the DDX3 ATP-binding site promotes DDX3-hnRNPK interaction and induces apoptosis.","method":"Co-immunoprecipitation with methylation mutants, apoptosis assays, in silico docking, domain-deletion constructs","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis-based Co-IP, domain dissection, functional apoptosis readout, follows on prior study, single lab","pmids":["34575922"],"is_preprint":false},{"year":2020,"finding":"hnRNPK and PTBP1 are essential RNA-binding proteins for SINEUP lncRNA function; they contribute to SINEUP sub-cellular distribution and assembly of translational initiation complexes, leading to enhanced target mRNA translation.","method":"Co-transfection, co-localization imaging, siRNA knockdown, polysome/translational complex analysis","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with translational readout, co-localization, complex assembly assays, single lab","pmids":["33130894"],"is_preprint":false},{"year":2019,"finding":"hnRNPK decreases α-tubulin K40 acetylation in cells by downregulating HDAC6 expression; hnRNPK deficiency increases HDAC6 mRNA and protein, enhancing autophagosome-lysosome fusion and selective quality-control autophagy under basal (but not starvation) conditions.","method":"CRISPR-Cas9 KO, siRNA, overexpression, autophagy flux assays, co-localization, HDAC6 inhibitor rescue","journal":"International journal of oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO with inhibitor rescue, specific mechanistic link (HDAC6-tubulin acetylation-autophagy), single lab","pmids":["30106132"],"is_preprint":false},{"year":2020,"finding":"hnRNPK recognition of multi-cytosine-patch (C-patch) RNA is mediated cooperatively by multiple KH domains, with the RG/RGG domain providing essential contributions to RNA (but not DNA) binding affinity; KH3 alone is neither necessary nor sufficient. For the Xist B-repeat RNA, C-patch recognition is conformationally restricted within hairpin structures but relieved in unstructured RNA.","method":"In vitro binding assays with domain deletion mutants, quantitative RNA-protein interaction measurements, NMR-informed analysis, iCLIP crosslinking data analysis","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with domain mutants, multiple quantitative binding measurements, structural context analysis","pmids":["32813011"],"is_preprint":false}],"current_model":"HNRNPK is a multifunctional RNA/DNA-binding protein whose activities are tightly regulated by post-translational modifications (ERK-mediated phosphorylation at S284/S353 driving cytoplasmic accumulation and translational repression; SUMOylation by PIAS3/SENP2 controlling p53 co-activator function; arginine methylation at R296/R299 modulating PKCδ-dependent apoptosis; Aurora-A phosphorylation at S379 disrupting p53 interaction; O-GlcNAcylation promoting nuclear translocation; K63-linked ubiquitylation by SCFFbxo4 limiting mRNA binding): in the nucleus it acts as a transcriptional co-activator of p53, binds single-stranded promoter DNA to repress transcription, regulates alternative splicing (e.g., MRPL33, CD44E via SRSF1), and recruits PCGF3/5-PRC1 to the Xist B-repeat to establish X-chromosome silencing; in the cytoplasm it represses translation of DICE-element-containing mRNAs, promotes IRES-dependent MYC translation, protects specific mRNAs from degradation (GADD45A, JUND) or targets others for decay (Hif1a, WWC1 mRNA), and regulates cell spreading/migration by directly inhibiting N-WASP through its KI domain."},"narrative":{"mechanistic_narrative":"HNRNPK is a multifunctional KH-domain RNA/DNA-binding protein that integrates signaling inputs with post-transcriptional and transcriptional gene control across proliferation, differentiation, apoptosis, and chromatin silencing [PMID:11231586, PMID:31519929]. It recognizes cytosine-rich (C-patch) sequences cooperatively through its multiple KH domains, with the RG/RGG domain providing essential affinity for RNA but not DNA, and C-patch accessibility is gated by RNA secondary structure [PMID:32813011]. Subcellular partitioning is the central control point: MAPK/ERK phosphorylation at S284/S353 drives cytoplasmic accumulation required for translational repression of DICE-element mRNAs [PMID:11231586], while O-GlcNAcylation promotes nuclear translocation [PMID:30444036]. In the nucleus HNRNPK functions as a transcriptional co-activator of p53 — UV-induced SUMOylation by PIAS3 (reversed by SENP2) stabilizes it and shifts its affinity toward p53 to drive p21-mediated cell-cycle arrest [PMID:23092970], an interaction independently disrupted by Aurora-A phosphorylation at S379 [PMID:21821029]. It also binds single-stranded promoter DNA with Purα to repress transcription [PMID:12411317] and recruits PCGF3/5-PRC1 to the Xist B-repeat to establish X-chromosome silencing [PMID:29220657]. In the cytoplasm it acts as a sequence-specific regulator of mRNA fate, repressing or activating translation depending on partner and modification state — promoting IRES-dependent MYC translation [PMID:16293596], stabilizing or destabilizing specific transcripts via its KH domains (e.g., promoting WWC1 and Hif1a mRNA decay [PMID:38414246, PMID:36127325]), and recruiting helicase partners such as DDX3X to activate JUND translation [PMID:31178390]. HNRNPK additionally regulates alternative splicing (e.g., MRPL33 isoform choice [PMID:28869607]) and directly inhibits N-WASP through its KI domain to control actin-based cell spreading and migration [PMID:16574661]. Its pro-oncogenic mRNA-binding activity is restrained by SCF-Fbxo4-mediated K63-linked ubiquitylation [PMID:36329064]. Loss of HNRNPK function is linked to cartilage and skeletal pathology through dysregulated Hippo signaling and glycolysis [PMID:38414246, PMID:36127325], and its activity counteracts C9orf72-associated RNA toxicity by transcriptionally controlling RRM2 to limit DNA damage [PMID:35895140].","teleology":[{"year":2001,"claim":"Established that ERK phosphorylation is the switch coupling extracellular signaling to HNRNPK's cytoplasmic translational-repressor function, defining subcellular partitioning as the core regulatory principle.","evidence":"In vitro kinase assay, S284/S353 mutagenesis, ERK inhibition and subcellular fractionation","pmids":["11231586"],"confidence":"High","gaps":["Did not identify the import/export machinery executing the relocalization","DICE-mRNA target repertoire not enumerated"]},{"year":2002,"claim":"Showed HNRNPK acts directly on chromatin as a transcriptional repressor by binding single-stranded promoter DNA with Purα, establishing a DNA-templated function distinct from its RNA roles.","evidence":"EMSA, transcriptional reporter assays and Co-IP at the CD43 promoter in K562 cells","pmids":["12411317"],"confidence":"Medium","gaps":["Mechanism of single-stranded DNA generation at the promoter unresolved","Genome-wide promoter occupancy not mapped"]},{"year":2005,"claim":"Linked HNRNPK's translation-regulatory (not transcription-regulatory) activity to oncogenic IRES-dependent MYC translation downstream of BCR/ABL-ERK signaling, separating its two functional arms.","evidence":"Dominant-negative dissection, IRES reporters and in vivo leukemogenesis assays","pmids":["16293596"],"confidence":"High","gaps":["Direct binding site within the MYC IRES not mapped","Co-factors for IRES activation not identified"]},{"year":2006,"claim":"Defined a non-nucleic-acid effector function: direct KI-domain inhibition of N-WASP, placing HNRNPK in cytoskeletal control of cell spreading and filopodia.","evidence":"Domain-mapped Co-IP, co-localization and spreading/filopodia assays","pmids":["16574661"],"confidence":"High","gaps":["Whether N-WASP regulation is coupled to HNRNPK's RNA roles unknown","Structural basis of KI–WH1 contact not solved"]},{"year":2012,"claim":"Established the SUMO switch (PIAS3/SENP2, ATR-dependent) that stabilizes HNRNPK and biases it toward p53 co-activation for p21-driven arrest, defining its DNA-damage co-activator function.","evidence":"SUMO-defective mutants, purified-protein binding assays and PIAS3/SENP2 knockdown","pmids":["23092970"],"confidence":"High","gaps":["SUMO acceptor lysine choreography with other PTMs not integrated","Promoter selectivity of the HNRNPK–p53 complex not defined here"]},{"year":2011,"claim":"Showed Aurora-A phosphorylation at S379 selectively disrupts the HNRNPK–p53 interaction without altering localization, providing a counter-regulatory brake on p53 transcriptional activity.","evidence":"In vitro kinase assay, Co-IP and S379 mutagenesis","pmids":["21821029"],"confidence":"Medium","gaps":["Single-lab finding without reciprocal in vivo validation","Interplay with SUMO-driven p53 stabilization untested"]},{"year":2014,"claim":"Demonstrated arginine methylation (R296/R299) suppresses adjacent PKCδ-mediated S302 phosphorylation to dampen apoptosis, revealing a PTM crosstalk node controlling cell death independently of p53.","evidence":"Methylation-defective mutants, in vitro kinase assays and apoptosis readouts in U2OS cells","pmids":["25104022"],"confidence":"High","gaps":["Responsible arginine methyltransferase not identified","Downstream apoptotic effectors not mapped"]},{"year":2017,"claim":"Identified HNRNPK as the principal Xist B-repeat (XR-PID) binding factor that recruits PCGF3/5-PRC1 to initiate X-chromosome silencing, defining a chromatin-establishing role bridging RNA recognition and Polycomb deposition.","evidence":"RNA deletion mutagenesis, knockdown, and synthetic tethering rescue with chromatin accessibility assays","pmids":["29220657"],"confidence":"High","gaps":["Molecular bridge between HNRNPK and PRC1 not biochemically defined","Contribution of HNRNPK PTMs to this activity untested"]},{"year":2017,"claim":"Showed HNRNPK governs both splicing isoform choice (MRPL33-L) and 3'UTR-mediated mRNA stability (PLK1, competing with miRNAs at a shared C-rich motif), establishing KH-domain C-patch recognition as the common engine of its post-transcriptional control.","evidence":"Knockdown/rescue epistasis, RT-PCR splicing assays, 3'UTR mutants, Ago2-IP and reporter assays","pmids":["28869607","28708135"],"confidence":"High","gaps":["Determinants selecting activation vs. repression at a given target unknown","miRNA competition generality across targets not established"]},{"year":2020,"claim":"Resolved the biochemical logic of target recognition: cooperative multi-KH C-patch binding with an essential RG/RGG contribution for RNA, gated by RNA structure, explaining differential RNA vs. DNA and structured vs. unstructured target engagement.","evidence":"In vitro domain-deletion binding assays, quantitative measurements and iCLIP/NMR-informed analysis on Xist B-repeat and C-patch RNAs","pmids":["32813011"],"confidence":"High","gaps":["High-resolution structure of the multi-KH–RNA complex not solved","How PTMs modulate C-patch affinity not tested"]},{"year":2022,"claim":"Established SCF-Fbxo4 K63-linked ubiquitylation as a brake on HNRNPK's mRNA-binding pro-oncogenic activity, connecting ubiquitin signaling to MYC translation and metastasis.","evidence":"Linkage-specific ubiquitylation assays, polysome profiling, genetic KO and invasion assays","pmids":["36329064"],"confidence":"High","gaps":["Ubiquitin acceptor sites not mapped","How K63 chains mechanically impair RNA binding unresolved"]},{"year":2022,"claim":"Defined HNRNPK-dependent destabilization of Hif1a (and later WWC1) mRNA via KH domains as physiologically essential for chondrocyte metabolism and cartilage homeostasis, linking its mRNA-decay activity to skeletal disease.","evidence":"Conditional KO mice, RIP, mRNA stability and metabolic assays; later WWC1 RNAi rescue in OA models","pmids":["36127325","38414246"],"confidence":"Medium","gaps":["Decay machinery recruited by HNRNPK at these targets not identified","Tissue-specific target selectivity mechanism unknown"]},{"year":null,"claim":"How the combinatorial PTM code (ERK/Src/Aurora-A phosphorylation, SUMO, arginine methylation, O-GlcNAc, K63-ubiquitin) is integrated to select among HNRNPK's transcriptional, splicing, translational, mRNA-stability, and cytoskeletal outputs at any given time and locus remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model relating PTM state to target choice","Structural basis of partner-switching between p53, N-WASP, DDX3X, and PRC1 unknown","Genome/transcriptome-wide direct target maps not integrated across conditions"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,1,10,15,17,32,33,40]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[14,26,40]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[2,12,14,26,31,34]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[0,5,15,38]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[6,25]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,38]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,14,28,35]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,6,8,18,19,24]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[1]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[6,8,19]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[23]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,13,17,33,40]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[2,12,14,26]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[2,7]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[1]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,5,8,18,22]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[3,37]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[25,31,32,33]}],"complexes":["hnRNPK-p53 transcriptional complex","PCGF3/5-PRC1 (recruited to Xist)"],"partners":["TP53","WASL","DDX3X","PIAS3","SENP2","YAP1","GSK3B","FBXO4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P61978","full_name":"Heterogeneous nuclear ribonucleoprotein K","aliases":["Transformation up-regulated nuclear protein","TUNP"],"length_aa":463,"mass_kda":51.0,"function":"One of the major pre-mRNA-binding proteins. Binds tenaciously to poly(C) sequences. Likely to play a role in the nuclear metabolism of hnRNAs, particularly for pre-mRNAs that contain cytidine-rich sequences. Can also bind poly(C) single-stranded DNA. Plays an important role in p53/TP53 response to DNA damage, acting at the level of both transcription activation and repression. When sumoylated, acts as a transcriptional coactivator of p53/TP53, playing a role in p21/CDKN1A and 14-3-3 sigma/SFN induction (By similarity). As far as transcription repression is concerned, acts by interacting with long intergenic RNA p21 (lincRNA-p21), a non-coding RNA induced by p53/TP53. This interaction is necessary for the induction of apoptosis, but not cell cycle arrest. As part of a ribonucleoprotein complex composed at least of ZNF827, HNRNPL and the circular RNA circZNF827 that nucleates the complex on chromatin, may negatively regulate the transcription of genes involved in neuronal differentiation (PubMed:33174841)","subcellular_location":"Cytoplasm; Nucleus, nucleoplasm; Cell projection, podosome","url":"https://www.uniprot.org/uniprotkb/P61978/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/HNRNPK","classification":"Common Essential","n_dependent_lines":1208,"n_total_lines":1208,"dependency_fraction":1.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"HNRNPL","stoichiometry":4.0},{"gene":"ATG13","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"CBX1","stoichiometry":0.2},{"gene":"CPSF6","stoichiometry":0.2},{"gene":"DDX21","stoichiometry":0.2},{"gene":"DHX9","stoichiometry":0.2},{"gene":"EMC9","stoichiometry":0.2},{"gene":"HNRNPD","stoichiometry":0.2},{"gene":"HNRNPH1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/HNRNPK","total_profiled":1310},"omim":[{"mim_id":"621463","title":"ZINC FINGER PROTEIN INTERACTING WITH K PROTEIN 1; ZIK1","url":"https://www.omim.org/entry/621463"},{"mim_id":"619370","title":"KH DOMAIN-CONTAINING PROTEIN 4, PRE-mRNA SPLICING FACTOR; KHDC4","url":"https://www.omim.org/entry/619370"},{"mim_id":"618710","title":"PARTNER OF NOB1; PNO1","url":"https://www.omim.org/entry/618710"},{"mim_id":"616580","title":"AU-KLINE SYNDROME; AUKS","url":"https://www.omim.org/entry/616580"},{"mim_id":"616492","title":"EWING SARCOMA-ASSOCIATED TRANSCRIPT 1, NONCODING; EWSAT1","url":"https://www.omim.org/entry/616492"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/HNRNPK"},"hgnc":{"alias_symbol":["CSBP","TUNP"],"prev_symbol":["HNRPK"]},"alphafold":{"accession":"P61978","domains":[{"cath_id":"3.30.310.210","chopping":"41-111_143-240","consensus_level":"medium","plddt":84.0159,"start":41,"end":240},{"cath_id":"3.30.1370.10","chopping":"387-458","consensus_level":"high","plddt":86.5343,"start":387,"end":458}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P61978","model_url":"https://alphafold.ebi.ac.uk/files/AF-P61978-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P61978-F1-predicted_aligned_error_v6.png","plddt_mean":64.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=HNRNPK","jax_strain_url":"https://www.jax.org/strain/search?query=HNRNPK"},"sequence":{"accession":"P61978","fasta_url":"https://rest.uniprot.org/uniprotkb/P61978.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P61978/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P61978"}},"corpus_meta":[{"pmid":"9207191","id":"PMC_9207191","title":"Novel homologues of CSBP/p38 MAP kinase: activation, substrate specificity and sensitivity to inhibition by pyridinyl imidazoles.","date":"1997","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/9207191","citation_count":431,"is_preprint":false},{"pmid":"8626550","id":"PMC_8626550","title":"Identification of mitogen-activated protein (MAP) kinase-activated protein kinase-3, a novel substrate of CSBP p38 MAP kinase.","date":"1996","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8626550","citation_count":303,"is_preprint":false},{"pmid":"29220657","id":"PMC_29220657","title":"hnRNPK Recruits PCGF3/5-PRC1 to the Xist RNA B-Repeat to Establish Polycomb-Mediated Chromosomal Silencing.","date":"2017","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/29220657","citation_count":264,"is_preprint":false},{"pmid":"11231586","id":"PMC_11231586","title":"ERK phosphorylation drives cytoplasmic accumulation of hnRNP-K and inhibition of mRNA translation.","date":"2001","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/11231586","citation_count":250,"is_preprint":false},{"pmid":"27012187","id":"PMC_27012187","title":"Long non-coding RNA CASC11 interacts with hnRNP-K and activates the WNT/β-catenin pathway to promote growth and metastasis in colorectal cancer.","date":"2016","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/27012187","citation_count":208,"is_preprint":false},{"pmid":"8902523","id":"PMC_8902523","title":"Differential activation of ERK, JNK/SAPK and P38/CSBP/RK map kinase family members during the cellular response to arsenite.","date":"1996","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/8902523","citation_count":185,"is_preprint":false},{"pmid":"9043657","id":"PMC_9043657","title":"Regulation of stress-induced cytokine production by pyridinylimidazoles; inhibition of CSBP kinase.","date":"1997","source":"Bioorganic & medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9043657","citation_count":171,"is_preprint":false},{"pmid":"16293596","id":"PMC_16293596","title":"A MAPK/HNRPK pathway controls BCR/ABL oncogenic potential by regulating MYC mRNA translation.","date":"2005","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/16293596","citation_count":161,"is_preprint":false},{"pmid":"38111678","id":"PMC_38111678","title":"Dissection of FOXO1-Induced LYPLAL1-DT Impeding Triple-Negative Breast Cancer Progression via Mediating hnRNPK/β-Catenin Complex.","date":"2023","source":"Research (Washington, D.C.)","url":"https://pubmed.ncbi.nlm.nih.gov/38111678","citation_count":150,"is_preprint":false},{"pmid":"31538344","id":"PMC_31538344","title":"The emerging roles of hnRNPK.","date":"2019","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/31538344","citation_count":131,"is_preprint":false},{"pmid":"24352616","id":"PMC_24352616","title":"PTEN antagonises Tcl1/hnRNPK-mediated G6PD pre-mRNA splicing which contributes to hepatocarcinogenesis.","date":"2013","source":"Gut","url":"https://pubmed.ncbi.nlm.nih.gov/24352616","citation_count":110,"is_preprint":false},{"pmid":"9873686","id":"PMC_9873686","title":"Pyrimidinylimidazole inhibitors of CSBP/p38 kinase demonstrating decreased inhibition of hepatic cytochrome P450 enzymes.","date":"1998","source":"Bioorganic & medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/9873686","citation_count":102,"is_preprint":false},{"pmid":"29410604","id":"PMC_29410604","title":"Exosomal lncRNA 91H is associated with poor development in colorectal cancer by modifying HNRNPK expression.","date":"2018","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/29410604","citation_count":102,"is_preprint":false},{"pmid":"21357748","id":"PMC_21357748","title":"Translation of myelin basic protein mRNA in oligodendrocytes is regulated by integrin activation and hnRNP-K.","date":"2011","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/21357748","citation_count":96,"is_preprint":false},{"pmid":"33619115","id":"PMC_33619115","title":"A TNFR2-hnRNPK Axis Promotes Primary Liver Cancer Development via Activation of YAP Signaling in Hepatic Progenitor Cells.","date":"2021","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/33619115","citation_count":95,"is_preprint":false},{"pmid":"8940070","id":"PMC_8940070","title":"Activation of the HIV-1 long terminal repeat by cytokines and environmental stress requires an active CSBP/p38 MAP kinase.","date":"1996","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8940070","citation_count":95,"is_preprint":false},{"pmid":"8107114","id":"PMC_8107114","title":"Identification, molecular cloning, expression and chromosome mapping of a family of transformation upregulated hnRNP-K proteins derived by alternative splicing.","date":"1994","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/8107114","citation_count":84,"is_preprint":false},{"pmid":"23564449","id":"PMC_23564449","title":"Heterogeneous nuclear ribonucleoprotein K (hnRNP-K) promotes tumor metastasis by induction of genes involved in extracellular matrix, cell movement, and angiogenesis.","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23564449","citation_count":84,"is_preprint":false},{"pmid":"29311158","id":"PMC_29311158","title":"Long Noncoding RNA pancEts-1 Promotes Neuroblastoma Progression through hnRNPK-Mediated β-Catenin Stabilization.","date":"2018","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/29311158","citation_count":83,"is_preprint":false},{"pmid":"30836866","id":"PMC_30836866","title":"Post-translational modification control of RNA-binding protein hnRNPK function.","date":"2019","source":"Open biology","url":"https://pubmed.ncbi.nlm.nih.gov/30836866","citation_count":81,"is_preprint":false},{"pmid":"30372559","id":"PMC_30372559","title":"LncRNA-OG Promotes the Osteogenic Differentiation of Bone Marrow-Derived Mesenchymal Stem Cells Under the Regulation of hnRNPK.","date":"2018","source":"Stem cells (Dayton, Ohio)","url":"https://pubmed.ncbi.nlm.nih.gov/30372559","citation_count":77,"is_preprint":false},{"pmid":"23092970","id":"PMC_23092970","title":"SUMOylation of hnRNP-K is required for p53-mediated cell-cycle arrest in response to DNA damage.","date":"2012","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/23092970","citation_count":74,"is_preprint":false},{"pmid":"35342346","id":"PMC_35342346","title":"PROX1 promotes breast cancer invasion and metastasis through WNT/β-catenin pathway via interacting with hnRNPK.","date":"2022","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35342346","citation_count":73,"is_preprint":false},{"pmid":"17483488","id":"PMC_17483488","title":"Loss-of-function screening by randomized intracellular antibodies: identification of hnRNP-K as a potential target for metastasis.","date":"2007","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/17483488","citation_count":71,"is_preprint":false},{"pmid":"30658384","id":"PMC_30658384","title":"New Insights into the Interplay between Non-Coding RNAs and RNA-Binding Protein HnRNPK in Regulating Cellular Functions.","date":"2019","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/30658384","citation_count":69,"is_preprint":false},{"pmid":"33731207","id":"PMC_33731207","title":"CircFAM73A promotes the cancer stem cell-like properties of gastric cancer through the miR-490-3p/HMGA2 positive feedback loop and HNRNPK-mediated β-catenin stabilization.","date":"2021","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/33731207","citation_count":67,"is_preprint":false},{"pmid":"22815235","id":"PMC_22815235","title":"Identification of ZNF217, hnRNP-K, VEGF-A and IPO7 as targets for microRNAs that are downregulated in prostate carcinoma.","date":"2012","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/22815235","citation_count":65,"is_preprint":false},{"pmid":"30144205","id":"PMC_30144205","title":"Genomic analysis reveals recurrent deletion of JAK-STAT signaling inhibitors HNRNPK and SOCS1 in mycosis fungoides.","date":"2018","source":"Genes, chromosomes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/30144205","citation_count":62,"is_preprint":false},{"pmid":"26173930","id":"PMC_26173930","title":"GeneMatcher aids in the identification of a new malformation syndrome with intellectual disability, unique facial dysmorphisms, and skeletal and connective tissue abnormalities caused by de novo variants in HNRNPK.","date":"2015","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/26173930","citation_count":61,"is_preprint":false},{"pmid":"28869607","id":"PMC_28869607","title":"MRPL33 and its splicing regulator hnRNPK are required for mitochondria function and implicated in tumor progression.","date":"2017","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/28869607","citation_count":59,"is_preprint":false},{"pmid":"30428357","id":"PMC_30428357","title":"Smchd1 Targeting to the Inactive X Is Dependent on the Xist-HnrnpK-PRC1 Pathway.","date":"2018","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/30428357","citation_count":59,"is_preprint":false},{"pmid":"22015967","id":"PMC_22015967","title":"Regulation of neuroendocrine differentiation by AKT/hnRNPK/AR/β-catenin signaling in prostate cancer cells.","date":"2011","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/22015967","citation_count":56,"is_preprint":false},{"pmid":"25569684","id":"PMC_25569684","title":"Identification of HNRNPK as regulator of hepatitis C virus particle production.","date":"2015","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/25569684","citation_count":55,"is_preprint":false},{"pmid":"25236891","id":"PMC_25236891","title":"Withanone-rich combination of Ashwagandha withanolides restricts metastasis and angiogenesis through hnRNP-K.","date":"2014","source":"Molecular cancer therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/25236891","citation_count":53,"is_preprint":false},{"pmid":"25104022","id":"PMC_25104022","title":"Arginine methylation of hnRNPK negatively modulates apoptosis upon DNA damage through local regulation of phosphorylation.","date":"2014","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/25104022","citation_count":51,"is_preprint":false},{"pmid":"33931969","id":"PMC_33931969","title":"Caveolin-1-driven membrane remodelling regulates hnRNPK-mediated exosomal microRNA sorting in cancer.","date":"2021","source":"Clinical and translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33931969","citation_count":50,"is_preprint":false},{"pmid":"34314754","id":"PMC_34314754","title":"SGLT2 promotes pancreatic cancer progression by activating the Hippo signaling pathway via the hnRNPK-YAP1 axis.","date":"2021","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/34314754","citation_count":50,"is_preprint":false},{"pmid":"32065448","id":"PMC_32065448","title":"Circular RNA (circ-0075804) promotes the proliferation of retinoblastoma via combining heterogeneous nuclear ribonucleoprotein K (HNRNPK) to improve the stability of E2F transcription factor 3 E2F3.","date":"2020","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/32065448","citation_count":50,"is_preprint":false},{"pmid":"31519929","id":"PMC_31519929","title":"HNRNPK maintains epidermal progenitor function through transcription of proliferation genes and degrading differentiation promoting mRNAs.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/31519929","citation_count":49,"is_preprint":false},{"pmid":"33130894","id":"PMC_33130894","title":"SINEUP long non-coding RNA acts via PTBP1 and HNRNPK to promote translational initiation assemblies.","date":"2020","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/33130894","citation_count":48,"is_preprint":false},{"pmid":"34452628","id":"PMC_34452628","title":"Circ-GALNT16 restrains colorectal cancer progression by enhancing the SUMOylation of hnRNPK.","date":"2021","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/34452628","citation_count":47,"is_preprint":false},{"pmid":"18775702","id":"PMC_18775702","title":"African swine fever virus protein p30 interaction with heterogeneous nuclear ribonucleoprotein K (hnRNP-K) during infection.","date":"2008","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/18775702","citation_count":46,"is_preprint":false},{"pmid":"12411317","id":"PMC_12411317","title":"hnRNP-K and Pur(alpha) act together to repress the transcriptional activity of the CD43 gene promoter.","date":"2002","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/12411317","citation_count":45,"is_preprint":false},{"pmid":"24024157","id":"PMC_24024157","title":"Heme oxygenase-1 regulates postnatal lung repair after hyperoxia: role of β-catenin/hnRNPK signaling.","date":"2013","source":"Redox biology","url":"https://pubmed.ncbi.nlm.nih.gov/24024157","citation_count":42,"is_preprint":false},{"pmid":"26954065","id":"PMC_26954065","title":"A de novo frameshift in HNRNPK causing a Kabuki-like syndrome with nodular heterotopia.","date":"2016","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26954065","citation_count":41,"is_preprint":false},{"pmid":"26638989","id":"PMC_26638989","title":"Cytoplasmic hnRNPK interacts with GSK3β and is essential for the osteoclast differentiation.","date":"2015","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/26638989","citation_count":39,"is_preprint":false},{"pmid":"28423622","id":"PMC_28423622","title":"HnRNPK/miR-223/FBXW7 feedback cascade promotes pancreatic cancer cell growth and invasion.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/28423622","citation_count":38,"is_preprint":false},{"pmid":"32813011","id":"PMC_32813011","title":"hnRNPK recognition of the B motif of Xist and other biological RNAs.","date":"2020","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/32813011","citation_count":37,"is_preprint":false},{"pmid":"28708135","id":"PMC_28708135","title":"Regulation of PLK1 through competition between hnRNPK, miR-149-3p and miR-193b-5p.","date":"2017","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/28708135","citation_count":37,"is_preprint":false},{"pmid":"28335083","id":"PMC_28335083","title":"Down-regulation of DAB2IP promotes colorectal cancer invasion and metastasis by translocating hnRNPK into nucleus to enhance the transcription of MMP2.","date":"2017","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/28335083","citation_count":37,"is_preprint":false},{"pmid":"20587588","id":"PMC_20587588","title":"Comprehensive analysis of the palindromic motif TCTCGCGAGA: a regulatory element of the HNRNPK promoter.","date":"2010","source":"DNA research : an international journal for rapid publication of reports on genes and genomes","url":"https://pubmed.ncbi.nlm.nih.gov/20587588","citation_count":37,"is_preprint":false},{"pmid":"23798440","id":"PMC_23798440","title":"Anxiety-associated alternative polyadenylation of the serotonin transporter mRNA confers translational regulation by hnRNPK.","date":"2013","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/23798440","citation_count":36,"is_preprint":false},{"pmid":"31857793","id":"PMC_31857793","title":"hnRNPK promotes gastric tumorigenesis through regulating CD44E alternative splicing.","date":"2019","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/31857793","citation_count":35,"is_preprint":false},{"pmid":"31121493","id":"PMC_31121493","title":"SERPINA3 is a key modulator of HNRNP-K transcriptional activity against oxidative stress in HCC.","date":"2019","source":"Redox biology","url":"https://pubmed.ncbi.nlm.nih.gov/31121493","citation_count":34,"is_preprint":false},{"pmid":"30444036","id":"PMC_30444036","title":"O-GlcNAc-induced nuclear translocation of hnRNP-K is associated with progression and metastasis of cholangiocarcinoma.","date":"2019","source":"Molecular oncology","url":"https://pubmed.ncbi.nlm.nih.gov/30444036","citation_count":34,"is_preprint":false},{"pmid":"33731671","id":"PMC_33731671","title":"hnRNPK-regulated LINC00263 promotes malignant phenotypes through miR-147a/CAPN2.","date":"2021","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/33731671","citation_count":32,"is_preprint":false},{"pmid":"31178390","id":"PMC_31178390","title":"Metabolic stress activates an ERK/hnRNPK/DDX3X pathway in pancreatic β cells.","date":"2019","source":"Molecular metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/31178390","citation_count":32,"is_preprint":false},{"pmid":"29262567","id":"PMC_29262567","title":"HNRNPK inhibits gastric cancer cell proliferation through p53/p21/CCND1 pathway.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/29262567","citation_count":29,"is_preprint":false},{"pmid":"31329361","id":"PMC_31329361","title":"LncRNA RMST activates TAK1-mediated NF-κB signaling and promotes activation of microglial cells via competitively binding with hnRNPK.","date":"2019","source":"IUBMB life","url":"https://pubmed.ncbi.nlm.nih.gov/31329361","citation_count":29,"is_preprint":false},{"pmid":"32866608","id":"PMC_32866608","title":"Lnc-FAM84B-4 acts as an oncogenic lncRNA by interacting with protein hnRNPK to restrain MAPK phosphatases-DUSP1 expression.","date":"2020","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/32866608","citation_count":29,"is_preprint":false},{"pmid":"31852624","id":"PMC_31852624","title":"LncRNA RMST-mediated miR-107 transcription promotes OGD-induced neuronal apoptosis via interacting with hnRNPK.","date":"2019","source":"Neurochemistry international","url":"https://pubmed.ncbi.nlm.nih.gov/31852624","citation_count":28,"is_preprint":false},{"pmid":"26972480","id":"PMC_26972480","title":"hnRNPK inhibits GSK3β Ser9 phosphorylation, thereby stabilizing c-FLIP and contributes to TRAIL resistance in H1299 lung adenocarcinoma cells.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/26972480","citation_count":28,"is_preprint":false},{"pmid":"36130591","id":"PMC_36130591","title":"An HNRNPK-specific DNA methylation signature makes sense of missense variants and expands the phenotypic spectrum of Au-Kline syndrome.","date":"2022","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36130591","citation_count":27,"is_preprint":false},{"pmid":"32585241","id":"PMC_32585241","title":"FGD5-AS1 facilitates glioblastoma progression by activation of Wnt/β-catenin signaling via regulating miR-129-5p/HNRNPK axis.","date":"2020","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32585241","citation_count":27,"is_preprint":false},{"pmid":"27424288","id":"PMC_27424288","title":"Nujiangexathone A, a novel compound from Garcinia nujiangensis, suppresses cervical cancer growth by targeting hnRNPK.","date":"2016","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/27424288","citation_count":26,"is_preprint":false},{"pmid":"16574661","id":"PMC_16574661","title":"Interaction of N-WASP with hnRNPK and its role in filopodia formation and cell spreading.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16574661","citation_count":26,"is_preprint":false},{"pmid":"26530384","id":"PMC_26530384","title":"EtpE Binding to DNase X Induces Ehrlichial Entry via CD147 and hnRNP-K Recruitment, Followed by Mobilization of N-WASP and Actin.","date":"2015","source":"mBio","url":"https://pubmed.ncbi.nlm.nih.gov/26530384","citation_count":26,"is_preprint":false},{"pmid":"21821029","id":"PMC_21821029","title":"Aurora-A phosphorylates hnRNPK and disrupts its interaction with p53.","date":"2011","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/21821029","citation_count":25,"is_preprint":false},{"pmid":"38238853","id":"PMC_38238853","title":"LINC00571 drives tricarboxylic acid cycle metabolism in triple-negative breast cancer through HNRNPK/ILF2/IDH2 axis.","date":"2024","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/38238853","citation_count":24,"is_preprint":false},{"pmid":"28374925","id":"PMC_28374925","title":"Clinical spectrum of Kabuki-like syndrome caused by HNRNPK haploinsufficiency.","date":"2017","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28374925","citation_count":24,"is_preprint":false},{"pmid":"15962305","id":"PMC_15962305","title":"Compartmentalization of hnRNP-K during cell cycle progression and its interaction with calponin in the cytoplasm.","date":"2005","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15962305","citation_count":24,"is_preprint":false},{"pmid":"36439880","id":"PMC_36439880","title":"HNRNPK/CLCN3 axis facilitates the progression of LUAD through CAF-tumor interaction.","date":"2022","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36439880","citation_count":23,"is_preprint":false},{"pmid":"35895140","id":"PMC_35895140","title":"HNRNPK alleviates RNA toxicity by counteracting DNA damage in C9orf72 ALS.","date":"2022","source":"Acta neuropathologica","url":"https://pubmed.ncbi.nlm.nih.gov/35895140","citation_count":22,"is_preprint":false},{"pmid":"28426877","id":"PMC_28426877","title":"Knockdown of hnRNPK leads to increased DNA damage after irradiation and reduces survival of tumor cells.","date":"2017","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/28426877","citation_count":22,"is_preprint":false},{"pmid":"26305187","id":"PMC_26305187","title":"RTVP-1 regulates glioma cell migration and invasion via interaction with N-WASP and hnRNPK.","date":"2015","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/26305187","citation_count":21,"is_preprint":false},{"pmid":"34761103","id":"PMC_34761103","title":"DNA-methylation-induced silencing of DIO3OS drives non-small cell lung cancer progression via activating hnRNPK-MYC-CDC25A axis.","date":"2021","source":"Molecular therapy oncolytics","url":"https://pubmed.ncbi.nlm.nih.gov/34761103","citation_count":21,"is_preprint":false},{"pmid":"38654325","id":"PMC_38654325","title":"Tumor-suppressive miR-4732-3p is sorted into fucosylated exosome by hnRNPK to avoid the inhibition of lung cancer progression.","date":"2024","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/38654325","citation_count":21,"is_preprint":false},{"pmid":"24373910","id":"PMC_24373910","title":"Transcriptome sequencing of Chinese and Caucasian population identifies ethnic-associated differential transcript abundance of heterogeneous nuclear ribonucleoprotein K (hnRNPK).","date":"2013","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/24373910","citation_count":21,"is_preprint":false},{"pmid":"36681772","id":"PMC_36681772","title":"Single-cell RNA binding protein regulatory network analyses reveal oncogenic HNRNPK-MYC signalling pathway in cancer.","date":"2023","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/36681772","citation_count":19,"is_preprint":false},{"pmid":"30106132","id":"PMC_30106132","title":"hnRNPK modulates selective quality-control autophagy by downregulating the expression of HDAC6 in 293 cells.","date":"2018","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/30106132","citation_count":19,"is_preprint":false},{"pmid":"29898807","id":"PMC_29898807","title":"The multifunctional RNA-binding protein hnRNPK is critical for the proliferation and differentiation of myoblasts.","date":"2018","source":"BMB reports","url":"https://pubmed.ncbi.nlm.nih.gov/29898807","citation_count":18,"is_preprint":false},{"pmid":"24642125","id":"PMC_24642125","title":"The RNA binding protein hnRNP-K mediates post-transcriptional regulation of uncoupling protein-2 by angiopoietin-1.","date":"2014","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/24642125","citation_count":18,"is_preprint":false},{"pmid":"24508256","id":"PMC_24508256","title":"Accumulated SET protein up-regulates and interacts with hnRNPK, increasing its binding to nucleic acids, the Bcl-xS repression, and cellular proliferation.","date":"2014","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/24508256","citation_count":18,"is_preprint":false},{"pmid":"34575922","id":"PMC_34575922","title":"Arginine Methylation of hnRNPK Inhibits the DDX3-hnRNPK Interaction to Play an Anti-Apoptosis Role in Osteosarcoma Cells.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34575922","citation_count":17,"is_preprint":false},{"pmid":"19880579","id":"PMC_19880579","title":"hnRNP-K is a nuclear target of TCR-activated ERK and required for T-cell late activation.","date":"2009","source":"International immunology","url":"https://pubmed.ncbi.nlm.nih.gov/19880579","citation_count":17,"is_preprint":false},{"pmid":"31429522","id":"PMC_31429522","title":"miR-1249-3p accelerates the malignancy phenotype of hepatocellular carcinoma by directly targeting HNRNPK.","date":"2019","source":"Molecular genetics & genomic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31429522","citation_count":16,"is_preprint":false},{"pmid":"38414246","id":"PMC_38414246","title":"Hnrnpk protects against osteoarthritis through targeting WWC1 mRNA and inhibiting Hippo signaling pathway.","date":"2024","source":"Molecular therapy : the journal of the American Society of Gene Therapy","url":"https://pubmed.ncbi.nlm.nih.gov/38414246","citation_count":15,"is_preprint":false},{"pmid":"36329064","id":"PMC_36329064","title":"Tumor suppressor mediated ubiquitylation of hnRNPK is a barrier to oncogenic translation.","date":"2022","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/36329064","citation_count":15,"is_preprint":false},{"pmid":"35907898","id":"PMC_35907898","title":"LncRNA CRLM1 inhibits apoptosis and promotes metastasis through transcriptional regulation cooperated with hnRNPK in colorectal cancer.","date":"2022","source":"Cell & bioscience","url":"https://pubmed.ncbi.nlm.nih.gov/35907898","citation_count":15,"is_preprint":false},{"pmid":"33891563","id":"PMC_33891563","title":"SnoRD126 promotes the proliferation of hepatocellular carcinoma cells through transcriptional regulation of FGFR2 activation in combination with hnRNPK.","date":"2021","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/33891563","citation_count":15,"is_preprint":false},{"pmid":"35455958","id":"PMC_35455958","title":"Deletion of Hnrnpk Gene Causes Infertility in Male Mice by Disrupting Spermatogenesis.","date":"2022","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/35455958","citation_count":14,"is_preprint":false},{"pmid":"37460467","id":"PMC_37460467","title":"MGCG regulates glioblastoma tumorigenicity via hnRNPK/ATG2A and promotes autophagy.","date":"2023","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/37460467","citation_count":14,"is_preprint":false},{"pmid":"36127325","id":"PMC_36127325","title":"Hnrnpk maintains chondrocytes survival and function during growth plate development via regulating Hif1α-glycolysis axis.","date":"2022","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/36127325","citation_count":14,"is_preprint":false},{"pmid":"28228215","id":"PMC_28228215","title":"hnRNPK-regulated PTOV1-AS1 modulates heme oxygenase-1 expression via miR-1207-5p.","date":"2017","source":"BMB reports","url":"https://pubmed.ncbi.nlm.nih.gov/28228215","citation_count":14,"is_preprint":false},{"pmid":"30793470","id":"PMC_30793470","title":"Okamoto syndrome has features overlapping with Au-Kline syndrome and is caused by HNRNPK mutation.","date":"2019","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/30793470","citation_count":14,"is_preprint":false},{"pmid":"21190960","id":"PMC_21190960","title":"Hnrnpk, a protein differentially expressed in immature rat ovarian development, is required for normal primordial follicle assembly and development.","date":"2010","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/21190960","citation_count":14,"is_preprint":false},{"pmid":"36617174","id":"PMC_36617174","title":"BBOX1-AS1 mediates trophoblast cells dysfunction via regulating hnRNPK/GADD45A axis†.","date":"2023","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/36617174","citation_count":13,"is_preprint":false},{"pmid":"28756806","id":"PMC_28756806","title":"ERK1/2-mediated Cytoplasmic Accumulation of hnRNPK Antagonizes TRAIL-induced Apoptosis through Upregulation of XIAP in H1299 Cells.","date":"2017","source":"Biomedical and environmental sciences : BES","url":"https://pubmed.ncbi.nlm.nih.gov/28756806","citation_count":13,"is_preprint":false},{"pmid":"31998294","id":"PMC_31998294","title":"LncSSBP1 Functions as a Negative Regulator of IL-6 Through Interaction With hnRNPK in Bronchial Epithelial Cells Infected With Talaromyces marneffei.","date":"2020","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31998294","citation_count":13,"is_preprint":false},{"pmid":"17612614","id":"PMC_17612614","title":"Sequence and transcriptional study of HNRPK pseudogenes, and expression and molecular modeling analysis of hnRNP K isoforms.","date":"2007","source":"Genome","url":"https://pubmed.ncbi.nlm.nih.gov/17612614","citation_count":12,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50312,"output_tokens":10186,"usd":0.151863,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":20536,"output_tokens":4860,"usd":0.11209,"stage2_stop_reason":"end_turn"},"total_usd":0.263953,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"MAPK/ERK phosphorylates hnRNPK at serines 284 and 353 both in vitro and in vivo; this phosphorylation drives cytoplasmic accumulation of hnRNPK, which is required for its ability to silence mRNA translation of transcripts containing a differentiation-control element (DICE) in the 3' UTR. Mutation of ERK phosphoacceptor sites abolishes cytoplasmic accumulation and translational repression.\",\n      \"method\": \"In vitro kinase assay, site-directed mutagenesis, pharmacological ERK inhibition, subcellular fractionation, constitutively active MEK1 overexpression\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro phosphorylation assay with mutagenesis, multiple orthogonal approaches (mutant rescue, pharmacological inhibition, fractionation), single rigorous study\",\n      \"pmids\": [\"11231586\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"hnRNPK is the principal binding factor for the Xist RNA Polycomb Interaction Domain (XR-PID, encompassing the B-repeat element) and is required to recruit PCGF3/5-PRC1 to the inactive X chromosome. Deletion of XR-PID abolishes Polycomb recruitment, Xist-mediated gene silencing, and chromatin inaccessibility; synthetic tethering of hnRNPK to Xist RNA lacking XR-PID restores Polycomb recruitment.\",\n      \"method\": \"RNA deletion mutagenesis, hnRNPK knockdown, synthetic tethering rescue, chromatin accessibility assays, RNA-protein interaction studies\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal loss-of-function and rescue experiments establishing pathway position, replicated across approaches\",\n      \"pmids\": [\"29220657\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"UV-induced SUMOylation of hnRNPK by the E3 ligase PIAS3 (in an ATR-dependent manner) prevents HDM2-mediated ubiquitination and proteasomal degradation of hnRNPK, stabilizing it and increasing its affinity for p53 over HDM2, thereby enabling hnRNPK to act as a transcriptional co-activator of p53 for p21-mediated cell-cycle arrest. Later, SENP2 removes SUMO from hnRNPK, destabilizing it and releasing the cell-cycle arrest.\",\n      \"method\": \"SUMOylation-defective mutant analysis, purified SUMOylated hnRNPK binding assays, siRNA knockdown of PIAS3/SENP2, co-immunoprecipitation\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — biochemical reconstitution with purified proteins, mutagenesis, and multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"23092970\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Arginine methylation of hnRNPK at Arg296 and Arg299 inhibits nearby Ser302 phosphorylation mediated by the pro-apoptotic kinase PKCδ, thereby negatively regulating apoptosis following DNA damage. Cells expressing methylation-defective hnRNPK mutants show increased apoptosis through both intrinsic and extrinsic pathways in a p53-independent manner.\",\n      \"method\": \"Site-directed mutagenesis (Arg296/299), in vitro kinase assays, engineered U2OS cell lines, apoptosis assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — mutagenesis combined with multiple functional readouts and rescue experiments in a single rigorous study\",\n      \"pmids\": [\"25104022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"During oligodendrocyte differentiation and myelination, α6β1-integrin activation interacts with hnRNP-K, which binds MBP mRNA and translocates from the nucleus to the myelin sheath, reversing the inhibitory effect of the MBP mRNA 3'UTR on translation; knockdown of hnRNP-K inhibits MBP protein synthesis during myelination.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, subcellular fractionation/live imaging, in vitro translation assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, direct localization experiment with functional consequence, KD with specific phenotypic readout, multiple orthogonal methods\",\n      \"pmids\": [\"21357748\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"BCR/ABL activates hnRNPK expression and activity via the MAPK/ERK1/2 pathway; elevated hnRNPK enhances IRES-dependent MYC mRNA translation, contributing to leukemogenic proliferation and clonogenic potential. Interference with hnRNPK translation-regulatory activity (but not transcription-regulatory activity) impairs BCR/ABL-driven leukemogenesis.\",\n      \"method\": \"siRNA knockdown, dominant-negative constructs distinguishing translation vs. transcription functions, in vivo leukemogenesis assays, IRES reporter assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — specific domain dissection distinguishing translation from transcription function, in vitro and in vivo validation, multiple orthogonal methods\",\n      \"pmids\": [\"16293596\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"hnRNPK directly interacts with N-WASP via the WH1 domain of N-WASP and the KI domain of hnRNPK; co-expression of hnRNPK with N-WASP reverses N-WASP-stimulated cell spreading and reduces filopodia formation, identifying hnRNPK as a negative regulator of N-WASP at the spreading initiation center.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping, co-localization imaging, cell spreading and filopodia assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction mapped to specific domains, multiple functional readouts (spreading, filopodia), co-localization confirmed\",\n      \"pmids\": [\"16574661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Aurora-A kinase phosphorylates hnRNPK at serine 379; this phosphorylation disrupts the interaction of hnRNPK with p53 without affecting hnRNPK post-transcriptional activity or cellular localization, providing a mechanism by which Aurora-A reduces p53 transcriptional activity during DNA damage.\",\n      \"method\": \"In vitro kinase assay, co-immunoprecipitation, site-directed mutagenesis (S379)\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — reciprocal Co-IP and in vitro kinase assay with mutagenesis, single lab, single paper\",\n      \"pmids\": [\"21821029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"During RANKL-induced osteoclast differentiation, PI3K/Akt-mediated Ser9 phosphorylation of GSK3β triggers ERK-dependent nuclear-to-cytoplasmic translocation of hnRNPK; cytoplasmic hnRNPK interacts with GSK3β and regulates NF-κB activation, NFATc1 expression, and tubulin acetylation, all critical for osteoclast differentiation. hnRNPK is also localized in the actin belt of mature osteoclasts.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation, siRNA knockdown, immunofluorescence localization, osteoclast differentiation assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, localization with functional consequence, knockdown with specific phenotypic readout, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"26638989\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HNRNPK is necessary for DDX6-mediated binding and degradation of a subset of mRNAs encoding differentiation-promoting transcription factors (GRHL3, KLF4, ZNF750) in epidermal progenitor cells, preventing premature differentiation. HNRNPK is also required for RNA Polymerase II binding to proliferation/self-renewal genes (MYC, CYR61, FGFR1, EGFR, cyclins) to sustain progenitor proliferative capacity.\",\n      \"method\": \"HNRNPK siRNA knockdown, RNA-seq, ChIP for RNA Pol II, mRNA stability assays, RIP for DDX6\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (ChIP, RIP, RNA-seq, KD), defines two distinct mechanistic roles, single lab\",\n      \"pmids\": [\"31519929\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"HNRNPK interacts directly with HCV RNA (but not Dengue virus RNA), and mutations that impair this RNA interaction also reduce HNRNPK's ability to suppress HCV particle production. In HCV-infected cells, HNRNPK is redistributed to sites adjacent to lipid droplets, co-localizing with core protein and HCV plus-strand RNA. The mechanism involves limiting viral RNA availability for incorporation into virions.\",\n      \"method\": \"siRNA knockdown, domain mapping rescue experiments, RNA-protein interaction assays, co-localization imaging, virion production assays\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown-rescue domain mapping, RNA binding-function correlation, co-localization, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"25569684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"hnRNPK, together with Tcl1, promotes G6PD pre-mRNA splicing and increases G6PD protein expression; PTEN forms a complex with hnRNPK and inhibits this G6PD pre-mRNA splicing, thereby antagonizing the Tcl1/hnRNPK-mediated enhancement of the pentose phosphate pathway in hepatocellular carcinoma.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, splicing assays, siRNA knockdown, biochemical complex analysis\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, mass spectrometry, splicing assays with knockdown, single lab\",\n      \"pmids\": [\"24352616\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"hnRNPK acts downstream of TNFα-TNFR2 signaling to directly interact with and stabilize YAP on target gene promoters genome-wide, co-regulating YAP target gene expression in hepatic progenitor cells. TNFR1 does not mediate this effect.\",\n      \"method\": \"Co-immunoprecipitation, ChIP-seq, siRNA knockdown, single-cell RNA sequencing\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide ChIP-seq, Co-IP, and KD with specific phenotypic readout, single lab\",\n      \"pmids\": [\"33619115\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"hnRNPK regulates alternative splicing of MRPL33 pre-mRNA to promote inclusion of exon 3, producing the long isoform MRPL33-L; knockdown of hnRNPK phenocopies MRPL33-L depletion (impaired proliferation, increased apoptosis, mitochondrial dysfunction), and overexpression of MRPL33-L can rescue hnRNPK-depleted cells, placing hnRNPK upstream of MRPL33-L in a cancer-relevant splicing pathway.\",\n      \"method\": \"siRNA knockdown, overexpression rescue, RT-PCR splicing assay, mitochondrial functional assays, xenograft model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — epistasis established by rescue, multiple functional readouts both in vitro and in vivo, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"28869607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"hnRNP-K and Purα act together to repress transcriptional activity of the CD43 gene promoter during K562 cell activation by binding single-stranded DNA sequences in the promoter.\",\n      \"method\": \"Transcriptional reporter assays, electrophoretic mobility shift assays (EMSA), co-immunoprecipitation\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA plus reporter assays, protein-DNA binding and co-IP, single lab\",\n      \"pmids\": [\"12411317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In pancreatic β cells under glucolipotoxic metabolic stress, MEK/ERK signaling phosphorylates hnRNPK, which then binds the 3'UTR poly-C motif of JUND mRNA and recruits the RNA helicase DDX3X as a binding partner to promote efficient JUND mRNA translation. Loss of hnRNPK blocks post-transcriptional JUND upregulation, and hnRNPK loss reduces DDX3X association with translation machinery.\",\n      \"method\": \"RNA immunoprecipitation, co-immunoprecipitation, Phos-tag analysis, TRAP-qPCR, CRISPR-Cas9 KO, lentiviral delivery\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (RIP, Co-IP, Phos-tag, TRAP), functional validation in primary islets and cell line, single lab\",\n      \"pmids\": [\"31178390\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"hnRNP-K promotes tumor metastasis by regulating extracellular matrix, cell motility, and angiogenesis gene-expression pathways (including Cck, Mmp-3, Ptgs2, and Ctgf), as established in hnRNP-K-overexpressing and -underexpressing cell lines with in vitro and in vivo metastasis assays.\",\n      \"method\": \"Stable hnRNPK overexpression/knockdown cell lines, cDNA microarray, pathway analysis, in vivo metastasis assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with in vivo validation, pathway-level mechanistic dissection, single lab\",\n      \"pmids\": [\"23564449\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"hnRNPK regulates PLK1 expression post-transcriptionally through KH1- and KH2-dependent interactions with cytosine-rich sequences in the 3'UTR of PLK1 mRNA, and competes with miR-149-3p and miR-193b-5p for this shared C-rich motif to influence PLK1 mRNA stability and Ago2 association.\",\n      \"method\": \"siRNA knockdown, overexpression, Ago2 immunoprecipitation, 3'UTR deletion mutants, luciferase reporter assays\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mapping (KH1/KH2), competition with miRNAs at defined motif, Ago2-IP, single lab\",\n      \"pmids\": [\"28708135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"hnRNPK translocated from nucleus to cytoplasm (via MAPK/ERK) binds to and inhibits Ser9 phosphorylation of GSK3β by PKC, thereby maintaining GSK3β in an active state that stabilizes c-FLIP protein and contributes to TRAIL resistance in H1299 lung adenocarcinoma cells.\",\n      \"method\": \"Subcellular fractionation, co-immunoprecipitation, co-localization imaging, GSK3β phosphorylation assays, c-FLIP stability assays, tissue microarray\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, localization with functional consequence, multiple signaling readouts, single lab\",\n      \"pmids\": [\"26972480\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Cytoplasmic hnRNP-K forms a multi-protein complex with calponin and ERK1/2 in smooth muscle cells; nuclear-to-cytoplasmic translocation of hnRNP-K is cell cycle-dependent, with cytoplasmic hnRNP-K appearing at later cell cycle stages, partly by translocation from the nucleus.\",\n      \"method\": \"Subcellular fractionation across cell cycle, cycloheximide chase, co-immunoprecipitation\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization experiment with functional context, Co-IP establishing complex, single lab\",\n      \"pmids\": [\"15962305\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"African swine fever virus protein p30 interacts with hnRNP-K through the KH1 and KH2 domains (residues 35–197) of hnRNP-K; this interaction occurs mainly in the nucleus, alters hnRNP-K subcellular distribution, and decreases nascent RNA synthesis in infected cells.\",\n      \"method\": \"Yeast two-hybrid, co-localization imaging, domain mapping, 5-fluorouridine incorporation assay\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — yeast two-hybrid with domain mapping, functional readout (RNA synthesis), co-localization, single lab\",\n      \"pmids\": [\"18775702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"hnRNP-K binds the distal polyadenylation element of SERT mRNA; Src-family kinase-mediated tyrosine phosphorylation of hnRNPK (induced by trophic factor S100β) is associated with increased SERT protein expression, suggesting hnRNPK holds SERT mRNA in a translationally repressed state that is relieved upon tyrosine phosphorylation.\",\n      \"method\": \"RNA-protein binding assays, genetic manipulation of hnRNPK, pharmacological Src inhibition, western blot for SERT protein\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct RNA binding, functional genetics, phosphorylation-function correlation, single lab\",\n      \"pmids\": [\"23798440\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Angiopoietin-1 stimulates Src-family kinase recruitment to hnRNP-K and tyrosine phosphorylation of hnRNP-K (requiring Tyr458); this phosphorylation prevents hnRNP-K from binding UCP2 mRNA, releasing it for translation and increasing UCP2 protein expression in endothelial cells without changing total UCP2 mRNA levels.\",\n      \"method\": \"In vitro Src phosphorylation of purified hnRNP-K, RIP, site-directed mutagenesis (Y458), co-immunoprecipitation, western blot\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro reconstitution with purified proteins, mutagenesis at specific residue, RIP and functional protein expression readout, single lab\",\n      \"pmids\": [\"24642125\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CAV1 (non-caveolar, in the absence of CAVIN1) drives localization of hnRNPK to multi-vesicular bodies (MVBs), recruiting AsUGnA motif-containing miRNAs for selective loading into exosomes; knockdown of hnRNPK abolishes PC3 extracellular vesicle-induced osteoclastogenesis, establishing hnRNPK as a miRNA sorting factor for exosomal release.\",\n      \"method\": \"hnRNPK knockdown, co-localization imaging, cholesterol depletion, miRNA pulldown, osteoclastogenesis assay\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — localization with functional consequence, knockdown with specific phenotypic readout, multiple orthogonal approaches, single lab\",\n      \"pmids\": [\"33931969\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"hnRNPK facilitates cytoplasmic interaction with and stabilization of β-catenin by inhibiting its proteasome-mediated degradation; lncRNA pancEts-1 promotes this interaction by binding hnRNPK and facilitating its physical interaction with β-catenin.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, proteasome inhibitor assays, lncRNA pulldown\",\n      \"journal\": \"Cancer research (reported in PMID:29311158)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP of hnRNPK-β-catenin complex, proteasome assay, single lab\",\n      \"pmids\": [\"29311158\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SCFFbxo4 E3 ubiquitin ligase restricts hnRNPK pro-oncogenic activity via K63-linked polyubiquitylation, limiting hnRNPK's ability to bind target mRNAs. Loss of SCFFbxo4 leads to hnRNPK-dependent increase in c-Myc mRNA translation, enhanced cell invasion, and tumor metastasis.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitylation assays (K63 linkage), polysome profiling, siRNA/genetic KO, invasion assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical ubiquitylation assay with linkage specificity, functional rescue experiments, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"36329064\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"hnRNPK activates transcription of the SRSF1 splicing regulator by binding to a motif upstream of the start codon (−65 to −77 site), thereby increasing expression of the oncogenic CD44E isoform (CD44v8-v10) in gastric cancer cells.\",\n      \"method\": \"ChIP assay, dual luciferase reporter assay, siRNA knockdown, RT-PCR splicing analysis\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and reporter assay define binding site, KD with splicing readout, single lab\",\n      \"pmids\": [\"31857793\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"hnRNP-K interacts with Ehrlichia entry-triggering protein EtpE-C via CD147 and cytoplasmic hnRNP-K; hnRNP-K activates N-WASP-dependent actin polymerization to drive bacterial entry. Functional ablation of cytoplasmic hnRNP-K by intracellular nanobody markedly attenuated Ehrlichia entry and infection.\",\n      \"method\": \"Affinity pulldown, far-Western blot, co-immunoprecipitation, shRNA knockdown, intracellular nanobody, in vitro actin polymerization assay, time-lapse imaging\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal validation methods including in vitro actin polymerization reconstitution, specific domain ablation, multiple independent validations\",\n      \"pmids\": [\"26530384\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"TCR-activated ERK phosphorylates hnRNP-K in the nucleus of T cells; hnRNP-K knockdown abrogates IL-2 production and causes increased proteolysis of Vav1 (a binding target of hnRNP-K), suggesting hnRNPK protects Vav1 from activation-induced degradation and is required for T cell activation.\",\n      \"method\": \"Proteomic analysis of TCR-activated nuclear proteins, siRNA knockdown, western blot for Vav1\",\n      \"journal\": \"International immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with specific functional readout (IL-2, Vav1 proteolysis), nuclear localization demonstrated, single lab\",\n      \"pmids\": [\"19880579\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"hnRNPK binds to the miR-223 promoter, and siRNA knockdown of hnRNPK reduces miR-223 levels in pancreatic cancer cells. FBXW7 interacts with hnRNPK and promotes its degradation via GSK3-mediated phosphorylation at threonine 1695, forming a feedback cascade.\",\n      \"method\": \"ChIP, siRNA knockdown, co-immunoprecipitation, GSK3 phosphorylation assay\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP for promoter binding, Co-IP for protein interaction, phosphorylation assay, single lab\",\n      \"pmids\": [\"28423622\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Circ-GALNT16 binds the KH3 domain of hnRNPK and promotes its SUMOylation, thereby enhancing formation of an hnRNPK-p53 transcriptional complex; SUMOylation of hnRNPK inhibited by SENP2 reduces sequence-specific DNA binding of the hnRNPK-p53 complex, regulating Serpine1 transcription.\",\n      \"method\": \"RNA pulldown, RIP, co-immunoprecipitation, ChIP, RNA sequencing, domain mapping (KH3)\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-specific RNA-protein interaction, SUMOylation-function link, ChIP, single lab\",\n      \"pmids\": [\"34452628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"hnRNPK alleviates RNA toxicity in C9orf72 ALS by counteracting DNA damage; HNRNPK subcellular localization (cytoplasmic mislocalization observed in patient cells) and RNA recognition are required for this function. hnRNPK transcriptionally controls RRM2 (ribonucleotide reductase regulatory subunit M2), and increasing either hnRNPK or RRM2 expression mitigates DNA damage in a C9orf72 RNA toxicity zebrafish model.\",\n      \"method\": \"Zebrafish overexpression model, patient fibroblasts/iPSC-derived motor neurons, post-mortem tissue, DNA damage assays, subcellular fractionation\",\n      \"journal\": \"Acta neuropathologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo model with rescue, patient tissue validation, subcellular localization with functional consequence, single lab\",\n      \"pmids\": [\"35895140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The KH1 and KH2 domains of hnRNPK bind and promote degradation of WWC1 mRNA; hnRNPK deletion increases WWC1 expression, activating Hippo signaling and aggravating osteoarthritis. Intra-articular AAV5-hnRNPK protects against OA, and WWC1 RNAi rescues cartilage degeneration caused by hnRNPK deletion.\",\n      \"method\": \"Conditional KO mice, AAV rescue, RIP/domain mapping, in vivo OA models, mRNA stability assays\",\n      \"journal\": \"Molecular therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-specific KH1/KH2 mechanism, in vivo genetic epistasis by rescue, single lab\",\n      \"pmids\": [\"38414246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"hnRNPK binds Hif1a mRNA and promotes its degradation via its KH domains; hnRNPK deletion in chondrocytes increases Hif1α protein, leading to exorbitant glycolysis and impaired chondrocyte survival and differentiation, causing dwarfism.\",\n      \"method\": \"Conditional chondrocyte KO mice, RIP, mRNA stability assay, metabolic assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP establishes direct mRNA binding, KO with in vivo phenotypic readout, single lab\",\n      \"pmids\": [\"36127325\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SGLT2 interacts with hnRNPK and promotes hnRNPK nuclear translocation, thereby enhancing hnRNPK-induced YAP1 transcription, activating Hippo signaling in pancreatic cancer cells.\",\n      \"method\": \"Liquid chromatography-mass spectrometry, co-immunoprecipitation, subcellular fractionation, siRNA knockdown, transcription reporter assay\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP validated by LC-MS, subcellular localization with functional consequence, single lab\",\n      \"pmids\": [\"34314754\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"O-GlcNAcylation of hnRNP-K is required for its nuclear translocation; suppression of O-GlcNAcylation retains hnRNP-K in the cytoplasm in cholangiocarcinoma cells, reducing their migratory capabilities.\",\n      \"method\": \"Click chemistry enzymatic labeling, LC-MS/MS proteomics, anti-OGP/anti-hnRNPK immunoprecipitation, sWGA pulldown, siRNA knockdown, subcellular fractionation\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mass spectrometry identification of modification, functional localization-migration link, multiple validation methods, single lab\",\n      \"pmids\": [\"30444036\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SET protein directly interacts with hnRNPK and increases hnRNPK's binding to nucleic acids; SET accumulation promotes hnRNPK nuclear localization and enhances Bcl-xS repression.\",\n      \"method\": \"Co-immunoprecipitation, overexpression/knockdown, nucleic acid binding assays, subcellular fractionation\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP/pulldown, single lab, limited mechanistic follow-up\",\n      \"pmids\": [\"24508256\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Arginine methylation of hnRNPK inhibits the DDX3-hnRNPK interaction; DDX3 C-terminus preferentially binds unmethylated hnRNPK and promotes apoptosis in osteosarcoma cells. A small molecule docking at the DDX3 ATP-binding site promotes DDX3-hnRNPK interaction and induces apoptosis.\",\n      \"method\": \"Co-immunoprecipitation with methylation mutants, apoptosis assays, in silico docking, domain-deletion constructs\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis-based Co-IP, domain dissection, functional apoptosis readout, follows on prior study, single lab\",\n      \"pmids\": [\"34575922\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"hnRNPK and PTBP1 are essential RNA-binding proteins for SINEUP lncRNA function; they contribute to SINEUP sub-cellular distribution and assembly of translational initiation complexes, leading to enhanced target mRNA translation.\",\n      \"method\": \"Co-transfection, co-localization imaging, siRNA knockdown, polysome/translational complex analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with translational readout, co-localization, complex assembly assays, single lab\",\n      \"pmids\": [\"33130894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"hnRNPK decreases α-tubulin K40 acetylation in cells by downregulating HDAC6 expression; hnRNPK deficiency increases HDAC6 mRNA and protein, enhancing autophagosome-lysosome fusion and selective quality-control autophagy under basal (but not starvation) conditions.\",\n      \"method\": \"CRISPR-Cas9 KO, siRNA, overexpression, autophagy flux assays, co-localization, HDAC6 inhibitor rescue\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO with inhibitor rescue, specific mechanistic link (HDAC6-tubulin acetylation-autophagy), single lab\",\n      \"pmids\": [\"30106132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"hnRNPK recognition of multi-cytosine-patch (C-patch) RNA is mediated cooperatively by multiple KH domains, with the RG/RGG domain providing essential contributions to RNA (but not DNA) binding affinity; KH3 alone is neither necessary nor sufficient. For the Xist B-repeat RNA, C-patch recognition is conformationally restricted within hairpin structures but relieved in unstructured RNA.\",\n      \"method\": \"In vitro binding assays with domain deletion mutants, quantitative RNA-protein interaction measurements, NMR-informed analysis, iCLIP crosslinking data analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with domain mutants, multiple quantitative binding measurements, structural context analysis\",\n      \"pmids\": [\"32813011\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HNRNPK is a multifunctional RNA/DNA-binding protein whose activities are tightly regulated by post-translational modifications (ERK-mediated phosphorylation at S284/S353 driving cytoplasmic accumulation and translational repression; SUMOylation by PIAS3/SENP2 controlling p53 co-activator function; arginine methylation at R296/R299 modulating PKCδ-dependent apoptosis; Aurora-A phosphorylation at S379 disrupting p53 interaction; O-GlcNAcylation promoting nuclear translocation; K63-linked ubiquitylation by SCFFbxo4 limiting mRNA binding): in the nucleus it acts as a transcriptional co-activator of p53, binds single-stranded promoter DNA to repress transcription, regulates alternative splicing (e.g., MRPL33, CD44E via SRSF1), and recruits PCGF3/5-PRC1 to the Xist B-repeat to establish X-chromosome silencing; in the cytoplasm it represses translation of DICE-element-containing mRNAs, promotes IRES-dependent MYC translation, protects specific mRNAs from degradation (GADD45A, JUND) or targets others for decay (Hif1a, WWC1 mRNA), and regulates cell spreading/migration by directly inhibiting N-WASP through its KI domain.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"HNRNPK is a multifunctional KH-domain RNA/DNA-binding protein that integrates signaling inputs with post-transcriptional and transcriptional gene control across proliferation, differentiation, apoptosis, and chromatin silencing [#0, #9]. It recognizes cytosine-rich (C-patch) sequences cooperatively through its multiple KH domains, with the RG/RGG domain providing essential affinity for RNA but not DNA, and C-patch accessibility is gated by RNA secondary structure [#40]. Subcellular partitioning is the central control point: MAPK/ERK phosphorylation at S284/S353 drives cytoplasmic accumulation required for translational repression of DICE-element mRNAs [#0], while O-GlcNAcylation promotes nuclear translocation [#35]. In the nucleus HNRNPK functions as a transcriptional co-activator of p53 — UV-induced SUMOylation by PIAS3 (reversed by SENP2) stabilizes it and shifts its affinity toward p53 to drive p21-mediated cell-cycle arrest [#2], an interaction independently disrupted by Aurora-A phosphorylation at S379 [#7]. It also binds single-stranded promoter DNA with Pur\\u03b1 to repress transcription [#14] and recruits PCGF3/5-PRC1 to the Xist B-repeat to establish X-chromosome silencing [#1]. In the cytoplasm it acts as a sequence-specific regulator of mRNA fate, repressing or activating translation depending on partner and modification state — promoting IRES-dependent MYC translation [#5], stabilizing or destabilizing specific transcripts via its KH domains (e.g., promoting WWC1 and Hif1a mRNA decay [#32, #33]), and recruiting helicase partners such as DDX3X to activate JUND translation [#15]. HNRNPK additionally regulates alternative splicing (e.g., MRPL33 isoform choice [#13]) and directly inhibits N-WASP through its KI domain to control actin-based cell spreading and migration [#6]. Its pro-oncogenic mRNA-binding activity is restrained by SCF-Fbxo4-mediated K63-linked ubiquitylation [#25]. Loss of HNRNPK function is linked to cartilage and skeletal pathology through dysregulated Hippo signaling and glycolysis [#32, #33], and its activity counteracts C9orf72-associated RNA toxicity by transcriptionally controlling RRM2 to limit DNA damage [#31].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established that ERK phosphorylation is the switch coupling extracellular signaling to HNRNPK's cytoplasmic translational-repressor function, defining subcellular partitioning as the core regulatory principle.\",\n      \"evidence\": \"In vitro kinase assay, S284/S353 mutagenesis, ERK inhibition and subcellular fractionation\",\n      \"pmids\": [\"11231586\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the import/export machinery executing the relocalization\", \"DICE-mRNA target repertoire not enumerated\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Showed HNRNPK acts directly on chromatin as a transcriptional repressor by binding single-stranded promoter DNA with Pur\\u03b1, establishing a DNA-templated function distinct from its RNA roles.\",\n      \"evidence\": \"EMSA, transcriptional reporter assays and Co-IP at the CD43 promoter in K562 cells\",\n      \"pmids\": [\"12411317\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of single-stranded DNA generation at the promoter unresolved\", \"Genome-wide promoter occupancy not mapped\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Linked HNRNPK's translation-regulatory (not transcription-regulatory) activity to oncogenic IRES-dependent MYC translation downstream of BCR/ABL-ERK signaling, separating its two functional arms.\",\n      \"evidence\": \"Dominant-negative dissection, IRES reporters and in vivo leukemogenesis assays\",\n      \"pmids\": [\"16293596\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct binding site within the MYC IRES not mapped\", \"Co-factors for IRES activation not identified\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined a non-nucleic-acid effector function: direct KI-domain inhibition of N-WASP, placing HNRNPK in cytoskeletal control of cell spreading and filopodia.\",\n      \"evidence\": \"Domain-mapped Co-IP, co-localization and spreading/filopodia assays\",\n      \"pmids\": [\"16574661\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether N-WASP regulation is coupled to HNRNPK's RNA roles unknown\", \"Structural basis of KI\\u2013WH1 contact not solved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Established the SUMO switch (PIAS3/SENP2, ATR-dependent) that stabilizes HNRNPK and biases it toward p53 co-activation for p21-driven arrest, defining its DNA-damage co-activator function.\",\n      \"evidence\": \"SUMO-defective mutants, purified-protein binding assays and PIAS3/SENP2 knockdown\",\n      \"pmids\": [\"23092970\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"SUMO acceptor lysine choreography with other PTMs not integrated\", \"Promoter selectivity of the HNRNPK\\u2013p53 complex not defined here\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed Aurora-A phosphorylation at S379 selectively disrupts the HNRNPK\\u2013p53 interaction without altering localization, providing a counter-regulatory brake on p53 transcriptional activity.\",\n      \"evidence\": \"In vitro kinase assay, Co-IP and S379 mutagenesis\",\n      \"pmids\": [\"21821029\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab finding without reciprocal in vivo validation\", \"Interplay with SUMO-driven p53 stabilization untested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrated arginine methylation (R296/R299) suppresses adjacent PKC\\u03b4-mediated S302 phosphorylation to dampen apoptosis, revealing a PTM crosstalk node controlling cell death independently of p53.\",\n      \"evidence\": \"Methylation-defective mutants, in vitro kinase assays and apoptosis readouts in U2OS cells\",\n      \"pmids\": [\"25104022\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Responsible arginine methyltransferase not identified\", \"Downstream apoptotic effectors not mapped\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified HNRNPK as the principal Xist B-repeat (XR-PID) binding factor that recruits PCGF3/5-PRC1 to initiate X-chromosome silencing, defining a chromatin-establishing role bridging RNA recognition and Polycomb deposition.\",\n      \"evidence\": \"RNA deletion mutagenesis, knockdown, and synthetic tethering rescue with chromatin accessibility assays\",\n      \"pmids\": [\"29220657\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular bridge between HNRNPK and PRC1 not biochemically defined\", \"Contribution of HNRNPK PTMs to this activity untested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed HNRNPK governs both splicing isoform choice (MRPL33-L) and 3'UTR-mediated mRNA stability (PLK1, competing with miRNAs at a shared C-rich motif), establishing KH-domain C-patch recognition as the common engine of its post-transcriptional control.\",\n      \"evidence\": \"Knockdown/rescue epistasis, RT-PCR splicing assays, 3'UTR mutants, Ago2-IP and reporter assays\",\n      \"pmids\": [\"28869607\", \"28708135\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants selecting activation vs. repression at a given target unknown\", \"miRNA competition generality across targets not established\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Resolved the biochemical logic of target recognition: cooperative multi-KH C-patch binding with an essential RG/RGG contribution for RNA, gated by RNA structure, explaining differential RNA vs. DNA and structured vs. unstructured target engagement.\",\n      \"evidence\": \"In vitro domain-deletion binding assays, quantitative measurements and iCLIP/NMR-informed analysis on Xist B-repeat and C-patch RNAs\",\n      \"pmids\": [\"32813011\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"High-resolution structure of the multi-KH\\u2013RNA complex not solved\", \"How PTMs modulate C-patch affinity not tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established SCF-Fbxo4 K63-linked ubiquitylation as a brake on HNRNPK's mRNA-binding pro-oncogenic activity, connecting ubiquitin signaling to MYC translation and metastasis.\",\n      \"evidence\": \"Linkage-specific ubiquitylation assays, polysome profiling, genetic KO and invasion assays\",\n      \"pmids\": [\"36329064\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitin acceptor sites not mapped\", \"How K63 chains mechanically impair RNA binding unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined HNRNPK-dependent destabilization of Hif1a (and later WWC1) mRNA via KH domains as physiologically essential for chondrocyte metabolism and cartilage homeostasis, linking its mRNA-decay activity to skeletal disease.\",\n      \"evidence\": \"Conditional KO mice, RIP, mRNA stability and metabolic assays; later WWC1 RNAi rescue in OA models\",\n      \"pmids\": [\"36127325\", \"38414246\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Decay machinery recruited by HNRNPK at these targets not identified\", \"Tissue-specific target selectivity mechanism unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the combinatorial PTM code (ERK/Src/Aurora-A phosphorylation, SUMO, arginine methylation, O-GlcNAc, K63-ubiquitin) is integrated to select among HNRNPK's transcriptional, splicing, translational, mRNA-stability, and cytoskeletal outputs at any given time and locus remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model relating PTM state to target choice\", \"Structural basis of partner-switching between p53, N-WASP, DDX3X, and PRC1 unknown\", \"Genome/transcriptome-wide direct target maps not integrated across conditions\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 1, 10, 15, 17, 32, 33, 40]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [14, 26, 40]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [2, 12, 14, 26, 31, 34]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [0, 5, 15, 38]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [6, 25]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 38]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 14, 28, 35]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 6, 8, 18, 19, 24]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [6, 8, 19]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [23]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 13, 17, 33, 40]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [2, 12, 14, 26]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [2, 7]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 5, 8, 18, 22]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [3, 37]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [25, 31, 32, 33]}\n    ],\n    \"complexes\": [\n      \"hnRNPK-p53 transcriptional complex\",\n      \"PCGF3/5-PRC1 (recruited to Xist)\"\n    ],\n    \"partners\": [\n      \"TP53\",\n      \"WASL\",\n      \"DDX3X\",\n      \"PIAS3\",\n      \"SENP2\",\n      \"YAP1\",\n      \"GSK3B\",\n      \"FBXO4\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}