{"gene":"UHMK1","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":1997,"finding":"KIS (UHMK1) was identified as a serine/threonine kinase possessing an RNP-type RNA recognition motif (UHM domain). KIS was originally isolated through its interaction with stathmin in a two-hybrid screen. Bacterially produced KIS has autophosphorylating activity and phosphorylates stathmin on serine residues, as well as myelin basic protein and synapsin in vitro. Immunofluorescence and biochemical fractionation showed KIS is partly targeted to the nucleus when overexpressed in HEK293 cells.","method":"Two-hybrid screen, in vitro kinase assay, immunofluorescence, biochemical fractionation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzymatic reconstitution with multiple substrates, two-hybrid identification of binding partner, direct localization experiment; foundational paper replicated by subsequent work","pmids":["9287318"],"is_preprint":false},{"year":2000,"finding":"KIS preferentially phosphorylates Ser-Pro motifs but has a specificity distinct from MAP kinases and CDKs. Mass spectrometry identified serine 164 of MBP as the unique site phosphorylated by KIS. A Ser-Pro motif in synapsin I was also phosphorylated. Histones inhibit KIS autophosphorylation.","method":"In vitro kinase assay, mass spectrometry, peptide sequencing, phosphopeptide mapping","journal":"European journal of biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay with mass spectrometry site identification, single lab but two orthogonal methods","pmids":["10880969"],"is_preprint":false},{"year":2007,"finding":"FoxM1 transcription factor directly regulates KIS expression in a growth factor-dependent manner. Loss of FoxM1 (deletion or siRNA) impairs KIS expression and leads to nuclear accumulation of p27(Kip1). KIS is a direct transcriptional target of FoxM1, providing a mechanism by which FoxM1 promotes cell cycle progression through p27 regulation.","method":"siRNA knockdown, FoxM1 deletion cells, immunoblotting, transcriptional reporter assay, promoter analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with defined cellular phenotype plus direct transcriptional target validation, single lab, two orthogonal methods","pmids":["17984092"],"is_preprint":false},{"year":2008,"finding":"The kinase domain of KIS is necessary for its nuclear localization, while the C-terminal UHM domain is required for binding to splicing factors SF1 and SF3b155. KIS binds SF1 and SF3b155 with efficiency similar to U2AF65 in pull-down assays. KIS shows different specificity for UHM docking sites in SF3b155 compared to other UHM-containing proteins.","method":"Subcellular localization of KIS deletion/mutation constructs, GST pull-down assays, co-immunoprecipitation","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — domain mapping by mutagenesis, reciprocal pull-down with splicing factors, single lab with multiple orthogonal methods","pmids":["18588901"],"is_preprint":false},{"year":2008,"finding":"KIS protects against vascular neointima formation by phosphorylating stathmin at serine 38, which promotes stathmin protein degradation and reduces cytoplasmic tubulin-destabilizing activity. KIS-/- mice show accelerated neointima formation after vascular injury, increased VSMC migration, increased stathmin levels, and abolished VSMC proliferation due to delayed nuclear export and degradation of p27Kip1. Downregulation of stathmin in KIS-/- VSMCs fully restored the normal phenotype.","method":"KIS knockout mice, vascular injury model, siRNA knockdown of stathmin, VSMC migration assay, immunoblotting, phosphorylation site identification","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — KIS knockout mouse model, genetic rescue by stathmin knockdown (epistasis), multiple orthogonal methods, in vivo validation","pmids":["19033656"],"is_preprint":false},{"year":2008,"finding":"KIS localizes to RNA granules in cortical neurons and colocalizes with the KIF3A kinesin and beta-actin mRNA. KIS interacts with KIF3A, NonO, and eEF1A (components of RNA granules) by co-immunoprecipitation from brain extracts. KIS knockdown impairs neurite outgrowth, and KIS kinase activity stimulates 3'UTR-dependent local translation in neuritic projections.","method":"Co-immunoprecipitation, live imaging/colocalization, siRNA knockdown, neurite outgrowth assay, local translation reporter assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP from brain extracts, colocalization, functional knockdown with defined readouts, single lab with multiple orthogonal methods","pmids":["19015237"],"is_preprint":false},{"year":2008,"finding":"KIS directly interacts with p27Kip1 protein and phosphorylates p27 at serine 10 (S10). Reduction of KIS by siRNA inhibits S10 phosphorylation, strongly suppresses cell proliferation, and increases the G0/G1 fraction in leukemia cells.","method":"Co-immunoprecipitation, siRNA knockdown, kinase assay, cell cycle analysis (flow cytometry), proliferation assay","journal":"Leukemia research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct interaction confirmed by Co-IP, functional siRNA knockdown with cell cycle phenotype, phosphorylation site mapping; consistent with prior literature","pmids":["18384876"],"is_preprint":false},{"year":2010,"finding":"Uhmk1 basally phosphorylates the cytosolic domain (CD) of PAM (peptidylglycine alpha-amidating monooxygenase), a secretory granule membrane enzyme. Uhmk1 is concentrated in the nucleus but cycles rapidly between nucleus and cytosol (FRAP). Phosphomimetic mutations in PAM-CD or simultaneous overexpression of active Uhmk1 reduces nuclear localization of soluble PAM-CD. Membrane-tethered Uhmk1 retains the ability to exclude PAM-CD from the nucleus, suggesting cytosolic Uhmk1 mediates this response. Uhmk1 knockdown increases POMC processing and reduces Aqp1 expression.","method":"FRAP (live imaging), phosphomimetic mutations, co-expression/overexpression, microarray analysis, immunofluorescence","journal":"Molecular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization by FRAP and functional mutations, but substrate phosphorylation site not mapped by mass spectrometry; single lab","pmids":["20573687"],"is_preprint":false},{"year":2011,"finding":"KIS phosphorylates p27 at Ser10 downstream of both the PI3K/Rac1 and ERK1/2 pathways in FGF-2-stimulated corneal endothelial cells. siRNA knockdown of KIS specifically inhibited Ser10 phosphorylation and FGF-2-stimulated cell proliferation. KIS expression was induced during early G1 by both pathways.","method":"siRNA knockdown of KIS, GTP pull-down (Rac1-GTP), immunoblotting for phospho-p27, MTT proliferation assay, Cdc25A and kinase inhibitors","journal":"Investigative ophthalmology & visual science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA loss-of-function with defined substrate and phenotype, pathway placement by pharmacological inhibitors, single lab","pmids":["20811053"],"is_preprint":false},{"year":2013,"finding":"CATS (FAM64A) protein was identified as a substrate of KIS/UHMK1. The interaction between CATS and KIS was confirmed by GST pull-down, co-immunoprecipitation, and colocalization. In vitro kinase assay mapped the KIS phosphorylation site to CATS serine 131 (S131). KIS and CATS expression change in opposite directions during the cell cycle. In a reporter assay, KIS enhanced the transcriptional repressor activity of CATS independently of S131 phosphorylation, and both CATS and KIS antagonize the transactivation capacity of CALM/AF10.","method":"Yeast two-hybrid screen, GST pull-down, co-immunoprecipitation, colocalization, in vitro kinase assay, phosphorylation site mapping, reporter gene assay","journal":"Biochimica et biophysica acta","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro kinase assay with phosphorylation site mapping, confirmed by Co-IP and pull-down, multiple orthogonal methods in a single study","pmids":["23419774"],"is_preprint":false},{"year":2014,"finding":"KIS downregulation in hippocampal neurons compromises spine development, alters actin dynamics, and reduces postsynaptic responsiveness. KIS absence decreases protein levels of PSD-95, GluR1, and GluR2 in a CPEB3-dependent manner. KIS counteracts the inhibitory activity of CPEB3 on GluR2 3'UTR translation and polyadenylation. KIS suppresses spine developmental defects caused by CPEB3 overexpression (genetic epistasis).","method":"KIS knockdown in mice, spine morphology analysis, biochemical fractionation, CPEB3 overexpression/rescue experiments, translation reporter assay","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (KIS/CPEB3 double manipulation), defined cellular phenotype with multiple readouts, multiple orthogonal methods","pmids":["25319695"],"is_preprint":false},{"year":2015,"finding":"MARCKS knockdown decreases KIS expression in VSMCs, leading to reduced phosphorylation of p27Kip1 at Ser10, nuclear trapping of p27Kip1, and cell cycle arrest. Overexpression of KIS (but not catalytically inactive KIS) rescues the p27Kip1 nuclear trapping and cell cycle arrest caused by MARCKS knockdown, establishing KIS kinase activity as the essential downstream effector of MARCKS in VSMC proliferation.","method":"siRNA knockdown, KIS overexpression with kinase-dead mutant, nuclear fractionation, BrdU incorporation, vascular injury model","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — catalytically inactive mutant rescue distinguishes kinase-dependent mechanism; single lab","pmids":["26528715"],"is_preprint":false},{"year":2019,"finding":"UHMK1 is a direct transcriptional target of YAP and FOXM1 in hepatocellular carcinoma cells. Using BioID labeling and mass spectrometry, MYBL2 (B-MYB) was identified as a direct UHMK1 interaction partner. UHMK1 stimulates nuclear enrichment of MYBL2, which promotes expression of cell cycle regulators CCNB1, CCNB2, KIF20A, and MAD2L1. This YAP-UHMK1-MYBL2 pathway was confirmed in YAPS127A-transgenic mice and human HCC tissues.","method":"BioID proximity labeling, mass spectrometry, co-immunoprecipitation, transcriptional reporter assay, nuclear fractionation, transgenic mouse model","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — BioID and MS for interaction partner identification, in vivo transgenic mouse validation, multiple orthogonal methods across multiple systems","pmids":["30936457"],"is_preprint":false},{"year":2020,"finding":"UHMK1 promotes gastric cancer progression by activating de novo purine synthesis. Mechanistically, UHMK1 phosphorylates NCOA3 at Ser1062 and Thr1067, which enhances NCOA3 binding to the transcription factor ATF4 and increases expression of purine metabolism genes. Phosphorylation-deficient NCOA3 (S1062A/T1067A) abrogates UHMK1-driven gastric cancer progression. Phospho-NCOA3 levels correlate with UHMK1 levels in human GC specimens.","method":"siRNA knockdown, phosphorylation site mutagenesis, co-immunoprecipitation, in vitro kinase assay, purine synthesis inhibitor rescue, xenograft models, human tissue analysis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — phosphorylation site mapping with mutational validation, rescue by pathway inhibitor, confirmed in vivo and in human tissue; multiple orthogonal methods","pmids":["31975428"],"is_preprint":false},{"year":2022,"finding":"UHMK1 interacts with STAT3 and enhances STAT3 transcriptional activity in colorectal cancer cells. STAT3 in turn transcriptionally activates UHMK1 expression, establishing a positive feedback regulatory loop. UHMK1 knockdown restrained CRC cell proliferation and increased oxaliplatin sensitivity, while overexpression had the opposite effects.","method":"Co-immunoprecipitation, siRNA knockdown, overexpression, transcriptional reporter assay, proliferation assay, drug sensitivity assay","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP demonstrates interaction; transcriptional feedback validated by reporter assay; single lab, mechanism of STAT3 activation not biochemically defined","pmids":["35501324"],"is_preprint":false},{"year":2022,"finding":"UHMK1 phosphorylates coilin (a major Cajal body component), alters Cajal body assembly and disassembly, and regulates alternative RNA splicing events that affect cell survival following 5-FU treatment in colon cancer cells.","method":"Phosphorylation assay, immunofluorescence (Cajal body morphology), alternative splicing analysis, cell viability assay","journal":"Cell communication and signaling","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — novel substrate (coilin) with phosphorylation assay and functional readout, but site not mapped by mutagenesis; single lab, single study","pmids":["35151311"],"is_preprint":false},{"year":2023,"finding":"UHMK1 is a splicing regulatory kinase. Global phosphoproteomic analysis upon UHMK1 modulation identified 163 differentially phosphorylated sites in 117 proteins, including 106 novel putative substrates enriched for spliceosome components. RNA-seq showed UHMK1 affects over 270 alternative splicing events. Splicing reporter assay confirmed UHMK1 function in splicing. UHMK1 knockdown had minor effects on transcript abundance but impacted epithelial-mesenchymal transition-related splicing.","method":"Global phosphoproteomics (MS), RNA-seq, splicing reporter assay, siRNA knockdown, bioinformatics","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — global phosphoproteomics with RNA-seq and functional splicing reporter, multiple orthogonal methods in one study; single lab","pmids":["36803961"],"is_preprint":false},{"year":2024,"finding":"KIS phosphorylates PTBP2 in neurons, counteracting PTBP2-mediated exon exclusion genome-wide during neuronal differentiation. Phosphorylation of unstructured domains within PTBP2 causes its dissociation from co-regulators Matrin3 and hnRNPM and reduces the RNA-binding capability of the complex. KIS and PTBP2 display strong opposing functional interactions in synaptic spine emergence and maturation (epistasis).","method":"In vitro kinase assay, RNA-seq, co-immunoprecipitation, RNA-binding assay, spine morphology analysis, genetic epistasis (double manipulation of KIS and PTBP2)","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro kinase assay with substrate identification, Co-IP for complex disruption, RNA-binding assay, genetic epistasis with functional readout; multiple orthogonal methods","pmids":["38597390"],"is_preprint":false},{"year":2024,"finding":"KIS (UHMK1) is transcriptionally activated by SOX4 in lung adenocarcinoma cells. KIS activates the β-catenin signaling pathway by modulating ID1. KIS overexpression promotes LUAD cell proliferation, migration, and invasion, while knockdown suppresses these phenotypes. Dual-luciferase assay confirmed transcriptional regulation of KIS by SOX4.","method":"Dual luciferase assay, RT-qPCR, western blot, siRNA knockdown, overexpression, xenograft model","journal":"Journal of cancer research and clinical oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — transcriptional regulation confirmed by luciferase assay, but ID1/β-catenin pathway connection not mechanistically dissected; single lab, single study","pmids":["39052126"],"is_preprint":false},{"year":2025,"finding":"UHMK1 phosphorylates NCOA3 (nuclear receptor coactivator 3), which activates ATF4 to upregulate MTHFD2 transcription in prostate cancer cells. MTHFD2 reciprocally enhances UHMK1 expression, forming a positive feedback loop. This was established by kinase assay, co-immunoprecipitation, and rescue experiments.","method":"Co-immunoprecipitation, in vitro kinase assay, siRNA knockdown, overexpression, xenograft model","journal":"Oncology research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — kinase assay and Co-IP support the mechanism, but phosphorylation site not mapped by mutagenesis; single lab, single study","pmids":["40918462"],"is_preprint":false},{"year":2026,"finding":"UHMK1 interacts with stathmin 1 (STMN1) in OSCC cells, confirmed by co-immunoprecipitation. UHMK1 stabilizes STMN1 protein expression by inhibiting its ubiquitin-proteasome degradation. UHMK1 and STMN1 together activate the PI3K/AKT/mTOR signaling pathway to regulate vasculogenic mimicry (VM) formation.","method":"Co-immunoprecipitation, ubiquitination assay (proteasome inhibitor), siRNA knockdown, VM formation assay, immunohistochemistry","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — Co-IP confirms interaction, proteasome inhibitor supports degradation mechanism, but ubiquitination sites and direct kinase-substrate relationship not established; single lab","pmids":["41966283"],"is_preprint":false}],"current_model":"UHMK1/KIS is a nuclear serine/threonine kinase with a unique UHM (U2AF homology motif) domain that serves dual roles in cell cycle regulation and RNA processing: it phosphorylates p27Kip1 at Ser10 to promote nuclear export and cell cycle progression, phosphorylates stathmin at Ser38 to regulate microtubule dynamics and cell migration, phosphorylates splicing factors SF1/SF3b155 and PTBP2 to control spliceosome assembly and alternative exon usage, and phosphorylates substrates such as NCOA3, coilin, and CATS to modulate transcription, Cajal body integrity, and cancer-related pathways; its expression is transcriptionally controlled by FoxM1 and YAP/FOXM1, and it localizes predominantly to the nucleus while cycling through the cytoplasm where it also associates with RNA granules to stimulate local translation in neurons."},"narrative":{"mechanistic_narrative":"UHMK1 (KIS) is a nuclear serine/threonine kinase, distinguished by a C-terminal UHM (U2AF homology motif) domain, that couples cell cycle control to RNA processing [PMID:9287318, PMID:18588901]. It preferentially phosphorylates Ser-Pro motifs with a specificity distinct from MAP kinases and CDKs [PMID:10880969]. A central function is phosphorylation of the CDK inhibitor p27Kip1 at Ser10, which drives nuclear export of p27 and permits cell cycle progression [PMID:18384876]; this activity sits downstream of FoxM1, which transcriptionally induces UHMK1 in a growth-factor-dependent manner, and of PI3K/Rac1 and ERK1/2 signaling [PMID:17984092, PMID:20811053]. UHMK1 also phosphorylates stathmin at Ser38 to promote its degradation and limit microtubule-destabilizing activity, a mechanism that restrains vascular smooth muscle cell migration and neointima formation in knockout mice [PMID:19033656]. Through its UHM domain UHMK1 binds the splicing factors SF1 and SF3b155 with U2AF65-like efficiency [PMID:18588901], and phosphoproteomic and RNA-seq analyses establish it as a splicing-regulatory kinase that targets spliceosome components and controls hundreds of alternative splicing events, including EMT-related exons [PMID:36803961]; in neurons it phosphorylates PTBP2, disrupting its complex with Matrin3 and hnRNPM and counteracting PTBP2-mediated exon exclusion during differentiation [PMID:38597390]. UHMK1 additionally localizes to neuronal RNA granules with KIF3A, NonO and eEF1A to stimulate local translation and support neurite outgrowth and spine development, in part by antagonizing the translational repressor CPEB3 [PMID:19015237, PMID:25319695]. In cancer, UHMK1 is induced by YAP/FOXM1 and SOX4 and acts through multiple effectors—enriching MYBL2 in the nucleus to drive cell cycle gene expression [PMID:30936457], phosphorylating NCOA3 to activate ATF4-dependent purine and one-carbon metabolism [PMID:31975428, PMID:40918462], and engaging STAT3 and stathmin-dependent signaling [PMID:35501324, PMID:41966283]. Additional substrates including CATS/FAM64A and the Cajal body protein coilin extend its reach to transcriptional repression and Cajal body dynamics [PMID:23419774, PMID:35151311].","teleology":[{"year":1997,"claim":"Establishing UHMK1 as a kinase with an RNA-recognition motif first defined the protein's dual identity, linking a stathmin-binding activity to a potential RNA-processing function.","evidence":"Two-hybrid identification of the stathmin interaction, in vitro kinase assays on stathmin/MBP/synapsin, and fractionation showing nuclear targeting","pmids":["9287318"],"confidence":"High","gaps":["In vitro substrates not yet validated as physiological","Functional role of the UHM/RRM domain undefined"]},{"year":2000,"claim":"Defining UHMK1's preference for Ser-Pro motifs, distinct from MAP kinases and CDKs, gave it a substrate-recognition logic and a mapped phosphosite on MBP.","evidence":"In vitro kinase assay with mass spectrometry and phosphopeptide mapping","pmids":["10880969"],"confidence":"High","gaps":["Consensus determined on model substrates, not endogenous targets","Regulation of autophosphorylation by histones not mechanistically explained"]},{"year":2007,"claim":"Identifying UHMK1 as a direct FoxM1 transcriptional target placed it within a growth-factor-driven program controlling p27Kip1 localization and cell cycle entry.","evidence":"FoxM1 deletion/siRNA, immunoblotting and promoter/reporter analysis in cells","pmids":["17984092"],"confidence":"High","gaps":["Direct kinase action on p27 not addressed in this study","Other upstream transcriptional inputs unexplored"]},{"year":2008,"claim":"Domain mapping showed the kinase domain drives nuclear localization while the UHM domain mediates SF1/SF3b155 binding, mechanistically tying UHMK1 to the spliceosome.","evidence":"Deletion/mutation localization constructs, GST pull-down and co-IP with splicing factors","pmids":["18588901"],"confidence":"High","gaps":["Whether SF1/SF3b155 are phosphorylation substrates not established here","Functional consequence for splicing not measured"]},{"year":2008,"claim":"The KIS knockout mouse established a physiological in vivo function: phosphorylation of stathmin Ser38 to limit VSMC migration and p27-dependent proliferation in vascular injury.","evidence":"KIS-/- mice in a vascular injury model with stathmin knockdown rescue (epistasis)","pmids":["19033656"],"confidence":"High","gaps":["Tissue-specific roles beyond vasculature not addressed","Balance between stathmin and p27 arms not quantified"]},{"year":2008,"claim":"Direct phosphorylation of p27Kip1 at Ser10 by UHMK1 connected its kinase activity to suppression of the G0/G1 arrest, demonstrated in leukemia cells.","evidence":"Co-IP, kinase assay, siRNA knockdown with cell cycle analysis","pmids":["18384876"],"confidence":"High","gaps":["Nuclear export step downstream of S10 not directly shown in this system"]},{"year":2008,"claim":"Localization to neuronal RNA granules with KIF3A, NonO and eEF1A revealed a cytoplasmic role in mRNA transport and local translation supporting neurite outgrowth.","evidence":"Co-IP from brain extracts, colocalization imaging, knockdown and local translation reporters","pmids":["19015237"],"confidence":"High","gaps":["Granule substrate(s) phosphorylated by KIS not identified","Mechanism coupling kinase activity to translation unclear"]},{"year":2010,"claim":"FRAP and substrate studies showed UHMK1 cycles rapidly between nucleus and cytosol, and cytosolic UHMK1 phosphorylates the PAM cytosolic domain to control its nuclear access and POMC processing.","evidence":"FRAP, phosphomimetic mutations, overexpression and microarray in endocrine cells","pmids":["20573687"],"confidence":"Medium","gaps":["PAM phosphorylation site not mapped by mass spectrometry","Direct kinase-substrate relationship inferred, not reconstituted"]},{"year":2011,"claim":"Placing UHMK1-driven p27 Ser10 phosphorylation downstream of PI3K/Rac1 and ERK1/2 integrated it into FGF-2-stimulated proliferative signaling.","evidence":"siRNA, Rac1-GTP pull-down, phospho-p27 immunoblot and proliferation assays with pathway inhibitors","pmids":["20811053"],"confidence":"Medium","gaps":["Direct linkage between the kinases and UHMK1 activation not biochemically defined","Single cell type"]},{"year":2013,"claim":"Identifying CATS/FAM64A as a Ser131 substrate and transcriptional partner extended UHMK1's influence to transcriptional repression and CALM/AF10 antagonism.","evidence":"Two-hybrid, pull-down, co-IP, in vitro kinase assay with site mapping and reporter assays","pmids":["23419774"],"confidence":"High","gaps":["Functional role of S131 phosphorylation unresolved (transcriptional effect was phosphorylation-independent)"]},{"year":2014,"claim":"In hippocampal neurons UHMK1 was shown to counteract CPEB3 repression of GluR2 translation, linking its kinase activity to spine development and synaptic strength.","evidence":"KIS knockdown, spine morphology, fractionation and CPEB3 epistasis/translation reporters","pmids":["25319695"],"confidence":"High","gaps":["Whether CPEB3 is a direct UHMK1 substrate not established","Molecular step relieving CPEB3 repression undefined"]},{"year":2015,"claim":"A MARCKS-UHMK1 axis was placed upstream of p27 control, with kinase-dead rescue confirming UHMK1 catalytic activity as the essential effector of VSMC proliferation.","evidence":"siRNA, kinase-dead rescue, nuclear fractionation, BrdU and vascular injury model","pmids":["26528715"],"confidence":"Medium","gaps":["Mechanism by which MARCKS controls UHMK1 levels not defined","Direct vs indirect MARCKS-UHMK1 link unclear"]},{"year":2019,"claim":"The YAP/FOXM1-UHMK1-MYBL2 axis defined an oncogenic role in hepatocellular carcinoma, with UHMK1 enriching MYBL2 in the nucleus to drive cell cycle genes.","evidence":"BioID/MS, co-IP, reporter assays, nuclear fractionation and YAP-transgenic mice with HCC tissue","pmids":["30936457"],"confidence":"High","gaps":["Whether MYBL2 is a phosphorylation substrate not shown","Mechanism of MYBL2 nuclear enrichment not defined"]},{"year":2020,"claim":"Mapping NCOA3 Ser1062/Thr1067 phosphorylation linked UHMK1 to ATF4-driven de novo purine synthesis and gastric cancer progression.","evidence":"Site mutagenesis, co-IP, in vitro kinase assay, pathway-inhibitor rescue, xenografts and human tissue","pmids":["31975428"],"confidence":"High","gaps":["Upstream signals activating this axis in tumors not defined"]},{"year":2022,"claim":"A UHMK1-STAT3 positive feedback loop was shown to support colorectal cancer proliferation and oxaliplatin resistance.","evidence":"Co-IP, knockdown/overexpression, reporter and drug-sensitivity assays","pmids":["35501324"],"confidence":"Medium","gaps":["Mechanism of STAT3 activation not biochemically defined","Whether STAT3 is a substrate unknown"]},{"year":2022,"claim":"Phosphorylation of coilin connected UHMK1 to Cajal body dynamics and 5-FU-responsive alternative splicing in colon cancer.","evidence":"Phosphorylation assay, immunofluorescence of Cajal bodies, splicing and viability assays","pmids":["35151311"],"confidence":"Medium","gaps":["Coilin phosphosite not mapped by mutagenesis","Single study, single lab"]},{"year":2023,"claim":"Global phosphoproteomics and RNA-seq established UHMK1 as a bona fide splicing-regulatory kinase targeting spliceosome components and controlling hundreds of alternative splicing events.","evidence":"Phosphoproteomics, RNA-seq, splicing reporter and siRNA in cells","pmids":["36803961"],"confidence":"High","gaps":["Direct vs indirect status of many putative substrates unverified","Functional consequences of individual splicing changes not dissected"]},{"year":2024,"claim":"Phosphorylation of PTBP2 provided a mechanistic basis for UHMK1's splicing control in neurons by dissociating PTBP2 from Matrin3/hnRNPM and reducing RNA binding during differentiation.","evidence":"In vitro kinase assay, RNA-seq, co-IP, RNA-binding assay and KIS/PTBP2 epistasis on spine maturation","pmids":["38597390"],"confidence":"High","gaps":["Specific phosphosites on PTBP2 not enumerated here","Generality to non-neuronal PTB proteins untested"]},{"year":2024,"claim":"SOX4 was identified as an additional transcriptional activator of UHMK1, with UHMK1 promoting lung adenocarcinoma growth via ID1/β-catenin signaling.","evidence":"Dual luciferase, RT-qPCR, western blot, knockdown/overexpression and xenografts","pmids":["39052126"],"confidence":"Low","gaps":["ID1/β-catenin connection not mechanistically dissected; single lab, single study","Direct UHMK1 substrate in this pathway unidentified"]},{"year":2025,"claim":"A UHMK1-NCOA3-ATF4-MTHFD2 axis with positive feedback extended the metabolic-coactivator mechanism to one-carbon metabolism in prostate cancer.","evidence":"Co-IP, in vitro kinase assay, knockdown/overexpression and xenografts","pmids":["40918462"],"confidence":"Medium","gaps":["NCOA3 phosphosite not mapped by mutagenesis in this study","Single lab, single study"]},{"year":2026,"claim":"UHMK1 was shown to stabilize STMN1 against proteasomal degradation and to co-activate PI3K/AKT/mTOR signaling driving vasculogenic mimicry in oral squamous cell carcinoma.","evidence":"Co-IP, ubiquitination/proteasome-inhibitor assay, knockdown, VM assay and IHC","pmids":["41966283"],"confidence":"Medium","gaps":["Ubiquitination sites and whether stabilization requires kinase activity not established","Reconciliation with prior stathmin-degradation role unaddressed"]},{"year":null,"claim":"How UHMK1 dynamically partitions between its nuclear cell-cycle/splicing functions and cytoplasmic RNA-granule/translation functions, and what governs substrate selection across these compartments, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model linking UHM-domain docking to substrate phosphorylation","Signals controlling nucleocytoplasmic cycling not defined","Direct vs indirect status of many proposed substrates unverified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,4,6,9,13,17]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,1,6,13,17]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[0]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,3,5]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,4,20]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,3,7]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[7]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[5]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[15]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[2,6,8,12]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[3,16,17]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[9,12,13]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[12,13,14]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[8,11,14,20]}],"complexes":[],"partners":["STMN1","CDKN1B","SF1","SF3B1","PTBP2","FAM64A","MYBL2","NCOA3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8TAS1","full_name":"Serine/threonine-protein kinase Kist","aliases":["Kinase interacting with stathmin","PAM COOH-terminal interactor protein 2","P-CIP2","U2AF homology motif kinase 1"],"length_aa":419,"mass_kda":46.5,"function":"Upon serum stimulation, phosphorylates CDKN1B/p27Kip1, thus controlling CDKN1B subcellular location and cell cycle progression in G1 phase. 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Section E, Crystallographic communications","url":"https://pubmed.ncbi.nlm.nih.gov/38584743","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.08.20.671397","title":"KICDB: A Causality-Oriented Multi-Omics Database for Kinase Inhibitor-Induced Cardiotoxicity","date":"2025-08-24","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.20.671397","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.09.16.25335898","title":"Status of anemia and its associated factors in patients with Type 2 Diabetes Mellitus at a tertiary hospital in Nepal: An Observational Cross Sectional Study","date":"2025-09-18","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.16.25335898","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":35995,"output_tokens":5810,"usd":0.097568,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14473,"output_tokens":6139,"usd":0.11292,"stage2_stop_reason":"end_turn"},"total_usd":0.210488,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"KIS (UHMK1) was identified as a serine/threonine kinase possessing an RNP-type RNA recognition motif (UHM domain). KIS was originally isolated through its interaction with stathmin in a two-hybrid screen. Bacterially produced KIS has autophosphorylating activity and phosphorylates stathmin on serine residues, as well as myelin basic protein and synapsin in vitro. Immunofluorescence and biochemical fractionation showed KIS is partly targeted to the nucleus when overexpressed in HEK293 cells.\",\n      \"method\": \"Two-hybrid screen, in vitro kinase assay, immunofluorescence, biochemical fractionation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzymatic reconstitution with multiple substrates, two-hybrid identification of binding partner, direct localization experiment; foundational paper replicated by subsequent work\",\n      \"pmids\": [\"9287318\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"KIS preferentially phosphorylates Ser-Pro motifs but has a specificity distinct from MAP kinases and CDKs. Mass spectrometry identified serine 164 of MBP as the unique site phosphorylated by KIS. A Ser-Pro motif in synapsin I was also phosphorylated. Histones inhibit KIS autophosphorylation.\",\n      \"method\": \"In vitro kinase assay, mass spectrometry, peptide sequencing, phosphopeptide mapping\",\n      \"journal\": \"European journal of biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay with mass spectrometry site identification, single lab but two orthogonal methods\",\n      \"pmids\": [\"10880969\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"FoxM1 transcription factor directly regulates KIS expression in a growth factor-dependent manner. Loss of FoxM1 (deletion or siRNA) impairs KIS expression and leads to nuclear accumulation of p27(Kip1). KIS is a direct transcriptional target of FoxM1, providing a mechanism by which FoxM1 promotes cell cycle progression through p27 regulation.\",\n      \"method\": \"siRNA knockdown, FoxM1 deletion cells, immunoblotting, transcriptional reporter assay, promoter analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with defined cellular phenotype plus direct transcriptional target validation, single lab, two orthogonal methods\",\n      \"pmids\": [\"17984092\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The kinase domain of KIS is necessary for its nuclear localization, while the C-terminal UHM domain is required for binding to splicing factors SF1 and SF3b155. KIS binds SF1 and SF3b155 with efficiency similar to U2AF65 in pull-down assays. KIS shows different specificity for UHM docking sites in SF3b155 compared to other UHM-containing proteins.\",\n      \"method\": \"Subcellular localization of KIS deletion/mutation constructs, GST pull-down assays, co-immunoprecipitation\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mapping by mutagenesis, reciprocal pull-down with splicing factors, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"18588901\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"KIS protects against vascular neointima formation by phosphorylating stathmin at serine 38, which promotes stathmin protein degradation and reduces cytoplasmic tubulin-destabilizing activity. KIS-/- mice show accelerated neointima formation after vascular injury, increased VSMC migration, increased stathmin levels, and abolished VSMC proliferation due to delayed nuclear export and degradation of p27Kip1. Downregulation of stathmin in KIS-/- VSMCs fully restored the normal phenotype.\",\n      \"method\": \"KIS knockout mice, vascular injury model, siRNA knockdown of stathmin, VSMC migration assay, immunoblotting, phosphorylation site identification\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KIS knockout mouse model, genetic rescue by stathmin knockdown (epistasis), multiple orthogonal methods, in vivo validation\",\n      \"pmids\": [\"19033656\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"KIS localizes to RNA granules in cortical neurons and colocalizes with the KIF3A kinesin and beta-actin mRNA. KIS interacts with KIF3A, NonO, and eEF1A (components of RNA granules) by co-immunoprecipitation from brain extracts. KIS knockdown impairs neurite outgrowth, and KIS kinase activity stimulates 3'UTR-dependent local translation in neuritic projections.\",\n      \"method\": \"Co-immunoprecipitation, live imaging/colocalization, siRNA knockdown, neurite outgrowth assay, local translation reporter assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP from brain extracts, colocalization, functional knockdown with defined readouts, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"19015237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"KIS directly interacts with p27Kip1 protein and phosphorylates p27 at serine 10 (S10). Reduction of KIS by siRNA inhibits S10 phosphorylation, strongly suppresses cell proliferation, and increases the G0/G1 fraction in leukemia cells.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, kinase assay, cell cycle analysis (flow cytometry), proliferation assay\",\n      \"journal\": \"Leukemia research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction confirmed by Co-IP, functional siRNA knockdown with cell cycle phenotype, phosphorylation site mapping; consistent with prior literature\",\n      \"pmids\": [\"18384876\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Uhmk1 basally phosphorylates the cytosolic domain (CD) of PAM (peptidylglycine alpha-amidating monooxygenase), a secretory granule membrane enzyme. Uhmk1 is concentrated in the nucleus but cycles rapidly between nucleus and cytosol (FRAP). Phosphomimetic mutations in PAM-CD or simultaneous overexpression of active Uhmk1 reduces nuclear localization of soluble PAM-CD. Membrane-tethered Uhmk1 retains the ability to exclude PAM-CD from the nucleus, suggesting cytosolic Uhmk1 mediates this response. Uhmk1 knockdown increases POMC processing and reduces Aqp1 expression.\",\n      \"method\": \"FRAP (live imaging), phosphomimetic mutations, co-expression/overexpression, microarray analysis, immunofluorescence\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by FRAP and functional mutations, but substrate phosphorylation site not mapped by mass spectrometry; single lab\",\n      \"pmids\": [\"20573687\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"KIS phosphorylates p27 at Ser10 downstream of both the PI3K/Rac1 and ERK1/2 pathways in FGF-2-stimulated corneal endothelial cells. siRNA knockdown of KIS specifically inhibited Ser10 phosphorylation and FGF-2-stimulated cell proliferation. KIS expression was induced during early G1 by both pathways.\",\n      \"method\": \"siRNA knockdown of KIS, GTP pull-down (Rac1-GTP), immunoblotting for phospho-p27, MTT proliferation assay, Cdc25A and kinase inhibitors\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA loss-of-function with defined substrate and phenotype, pathway placement by pharmacological inhibitors, single lab\",\n      \"pmids\": [\"20811053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CATS (FAM64A) protein was identified as a substrate of KIS/UHMK1. The interaction between CATS and KIS was confirmed by GST pull-down, co-immunoprecipitation, and colocalization. In vitro kinase assay mapped the KIS phosphorylation site to CATS serine 131 (S131). KIS and CATS expression change in opposite directions during the cell cycle. In a reporter assay, KIS enhanced the transcriptional repressor activity of CATS independently of S131 phosphorylation, and both CATS and KIS antagonize the transactivation capacity of CALM/AF10.\",\n      \"method\": \"Yeast two-hybrid screen, GST pull-down, co-immunoprecipitation, colocalization, in vitro kinase assay, phosphorylation site mapping, reporter gene assay\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro kinase assay with phosphorylation site mapping, confirmed by Co-IP and pull-down, multiple orthogonal methods in a single study\",\n      \"pmids\": [\"23419774\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"KIS downregulation in hippocampal neurons compromises spine development, alters actin dynamics, and reduces postsynaptic responsiveness. KIS absence decreases protein levels of PSD-95, GluR1, and GluR2 in a CPEB3-dependent manner. KIS counteracts the inhibitory activity of CPEB3 on GluR2 3'UTR translation and polyadenylation. KIS suppresses spine developmental defects caused by CPEB3 overexpression (genetic epistasis).\",\n      \"method\": \"KIS knockdown in mice, spine morphology analysis, biochemical fractionation, CPEB3 overexpression/rescue experiments, translation reporter assay\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (KIS/CPEB3 double manipulation), defined cellular phenotype with multiple readouts, multiple orthogonal methods\",\n      \"pmids\": [\"25319695\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MARCKS knockdown decreases KIS expression in VSMCs, leading to reduced phosphorylation of p27Kip1 at Ser10, nuclear trapping of p27Kip1, and cell cycle arrest. Overexpression of KIS (but not catalytically inactive KIS) rescues the p27Kip1 nuclear trapping and cell cycle arrest caused by MARCKS knockdown, establishing KIS kinase activity as the essential downstream effector of MARCKS in VSMC proliferation.\",\n      \"method\": \"siRNA knockdown, KIS overexpression with kinase-dead mutant, nuclear fractionation, BrdU incorporation, vascular injury model\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — catalytically inactive mutant rescue distinguishes kinase-dependent mechanism; single lab\",\n      \"pmids\": [\"26528715\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"UHMK1 is a direct transcriptional target of YAP and FOXM1 in hepatocellular carcinoma cells. Using BioID labeling and mass spectrometry, MYBL2 (B-MYB) was identified as a direct UHMK1 interaction partner. UHMK1 stimulates nuclear enrichment of MYBL2, which promotes expression of cell cycle regulators CCNB1, CCNB2, KIF20A, and MAD2L1. This YAP-UHMK1-MYBL2 pathway was confirmed in YAPS127A-transgenic mice and human HCC tissues.\",\n      \"method\": \"BioID proximity labeling, mass spectrometry, co-immunoprecipitation, transcriptional reporter assay, nuclear fractionation, transgenic mouse model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — BioID and MS for interaction partner identification, in vivo transgenic mouse validation, multiple orthogonal methods across multiple systems\",\n      \"pmids\": [\"30936457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"UHMK1 promotes gastric cancer progression by activating de novo purine synthesis. Mechanistically, UHMK1 phosphorylates NCOA3 at Ser1062 and Thr1067, which enhances NCOA3 binding to the transcription factor ATF4 and increases expression of purine metabolism genes. Phosphorylation-deficient NCOA3 (S1062A/T1067A) abrogates UHMK1-driven gastric cancer progression. Phospho-NCOA3 levels correlate with UHMK1 levels in human GC specimens.\",\n      \"method\": \"siRNA knockdown, phosphorylation site mutagenesis, co-immunoprecipitation, in vitro kinase assay, purine synthesis inhibitor rescue, xenograft models, human tissue analysis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — phosphorylation site mapping with mutational validation, rescue by pathway inhibitor, confirmed in vivo and in human tissue; multiple orthogonal methods\",\n      \"pmids\": [\"31975428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"UHMK1 interacts with STAT3 and enhances STAT3 transcriptional activity in colorectal cancer cells. STAT3 in turn transcriptionally activates UHMK1 expression, establishing a positive feedback regulatory loop. UHMK1 knockdown restrained CRC cell proliferation and increased oxaliplatin sensitivity, while overexpression had the opposite effects.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, overexpression, transcriptional reporter assay, proliferation assay, drug sensitivity assay\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP demonstrates interaction; transcriptional feedback validated by reporter assay; single lab, mechanism of STAT3 activation not biochemically defined\",\n      \"pmids\": [\"35501324\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"UHMK1 phosphorylates coilin (a major Cajal body component), alters Cajal body assembly and disassembly, and regulates alternative RNA splicing events that affect cell survival following 5-FU treatment in colon cancer cells.\",\n      \"method\": \"Phosphorylation assay, immunofluorescence (Cajal body morphology), alternative splicing analysis, cell viability assay\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — novel substrate (coilin) with phosphorylation assay and functional readout, but site not mapped by mutagenesis; single lab, single study\",\n      \"pmids\": [\"35151311\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"UHMK1 is a splicing regulatory kinase. Global phosphoproteomic analysis upon UHMK1 modulation identified 163 differentially phosphorylated sites in 117 proteins, including 106 novel putative substrates enriched for spliceosome components. RNA-seq showed UHMK1 affects over 270 alternative splicing events. Splicing reporter assay confirmed UHMK1 function in splicing. UHMK1 knockdown had minor effects on transcript abundance but impacted epithelial-mesenchymal transition-related splicing.\",\n      \"method\": \"Global phosphoproteomics (MS), RNA-seq, splicing reporter assay, siRNA knockdown, bioinformatics\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — global phosphoproteomics with RNA-seq and functional splicing reporter, multiple orthogonal methods in one study; single lab\",\n      \"pmids\": [\"36803961\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KIS phosphorylates PTBP2 in neurons, counteracting PTBP2-mediated exon exclusion genome-wide during neuronal differentiation. Phosphorylation of unstructured domains within PTBP2 causes its dissociation from co-regulators Matrin3 and hnRNPM and reduces the RNA-binding capability of the complex. KIS and PTBP2 display strong opposing functional interactions in synaptic spine emergence and maturation (epistasis).\",\n      \"method\": \"In vitro kinase assay, RNA-seq, co-immunoprecipitation, RNA-binding assay, spine morphology analysis, genetic epistasis (double manipulation of KIS and PTBP2)\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro kinase assay with substrate identification, Co-IP for complex disruption, RNA-binding assay, genetic epistasis with functional readout; multiple orthogonal methods\",\n      \"pmids\": [\"38597390\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KIS (UHMK1) is transcriptionally activated by SOX4 in lung adenocarcinoma cells. KIS activates the β-catenin signaling pathway by modulating ID1. KIS overexpression promotes LUAD cell proliferation, migration, and invasion, while knockdown suppresses these phenotypes. Dual-luciferase assay confirmed transcriptional regulation of KIS by SOX4.\",\n      \"method\": \"Dual luciferase assay, RT-qPCR, western blot, siRNA knockdown, overexpression, xenograft model\",\n      \"journal\": \"Journal of cancer research and clinical oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — transcriptional regulation confirmed by luciferase assay, but ID1/β-catenin pathway connection not mechanistically dissected; single lab, single study\",\n      \"pmids\": [\"39052126\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"UHMK1 phosphorylates NCOA3 (nuclear receptor coactivator 3), which activates ATF4 to upregulate MTHFD2 transcription in prostate cancer cells. MTHFD2 reciprocally enhances UHMK1 expression, forming a positive feedback loop. This was established by kinase assay, co-immunoprecipitation, and rescue experiments.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, siRNA knockdown, overexpression, xenograft model\",\n      \"journal\": \"Oncology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — kinase assay and Co-IP support the mechanism, but phosphorylation site not mapped by mutagenesis; single lab, single study\",\n      \"pmids\": [\"40918462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"UHMK1 interacts with stathmin 1 (STMN1) in OSCC cells, confirmed by co-immunoprecipitation. UHMK1 stabilizes STMN1 protein expression by inhibiting its ubiquitin-proteasome degradation. UHMK1 and STMN1 together activate the PI3K/AKT/mTOR signaling pathway to regulate vasculogenic mimicry (VM) formation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay (proteasome inhibitor), siRNA knockdown, VM formation assay, immunohistochemistry\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP confirms interaction, proteasome inhibitor supports degradation mechanism, but ubiquitination sites and direct kinase-substrate relationship not established; single lab\",\n      \"pmids\": [\"41966283\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"UHMK1/KIS is a nuclear serine/threonine kinase with a unique UHM (U2AF homology motif) domain that serves dual roles in cell cycle regulation and RNA processing: it phosphorylates p27Kip1 at Ser10 to promote nuclear export and cell cycle progression, phosphorylates stathmin at Ser38 to regulate microtubule dynamics and cell migration, phosphorylates splicing factors SF1/SF3b155 and PTBP2 to control spliceosome assembly and alternative exon usage, and phosphorylates substrates such as NCOA3, coilin, and CATS to modulate transcription, Cajal body integrity, and cancer-related pathways; its expression is transcriptionally controlled by FoxM1 and YAP/FOXM1, and it localizes predominantly to the nucleus while cycling through the cytoplasm where it also associates with RNA granules to stimulate local translation in neurons.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"UHMK1 (KIS) is a nuclear serine/threonine kinase, distinguished by a C-terminal UHM (U2AF homology motif) domain, that couples cell cycle control to RNA processing [#0, #3]. It preferentially phosphorylates Ser-Pro motifs with a specificity distinct from MAP kinases and CDKs [#1]. A central function is phosphorylation of the CDK inhibitor p27Kip1 at Ser10, which drives nuclear export of p27 and permits cell cycle progression [#6]; this activity sits downstream of FoxM1, which transcriptionally induces UHMK1 in a growth-factor-dependent manner, and of PI3K/Rac1 and ERK1/2 signaling [#2, #8]. UHMK1 also phosphorylates stathmin at Ser38 to promote its degradation and limit microtubule-destabilizing activity, a mechanism that restrains vascular smooth muscle cell migration and neointima formation in knockout mice [#4]. Through its UHM domain UHMK1 binds the splicing factors SF1 and SF3b155 with U2AF65-like efficiency [#3], and phosphoproteomic and RNA-seq analyses establish it as a splicing-regulatory kinase that targets spliceosome components and controls hundreds of alternative splicing events, including EMT-related exons [#16]; in neurons it phosphorylates PTBP2, disrupting its complex with Matrin3 and hnRNPM and counteracting PTBP2-mediated exon exclusion during differentiation [#17]. UHMK1 additionally localizes to neuronal RNA granules with KIF3A, NonO and eEF1A to stimulate local translation and support neurite outgrowth and spine development, in part by antagonizing the translational repressor CPEB3 [#5, #10]. In cancer, UHMK1 is induced by YAP/FOXM1 and SOX4 and acts through multiple effectors—enriching MYBL2 in the nucleus to drive cell cycle gene expression [#12], phosphorylating NCOA3 to activate ATF4-dependent purine and one-carbon metabolism [#13, #19], and engaging STAT3 and stathmin-dependent signaling [#14, #20]. Additional substrates including CATS/FAM64A and the Cajal body protein coilin extend its reach to transcriptional repression and Cajal body dynamics [#9, #15].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Establishing UHMK1 as a kinase with an RNA-recognition motif first defined the protein's dual identity, linking a stathmin-binding activity to a potential RNA-processing function.\",\n      \"evidence\": \"Two-hybrid identification of the stathmin interaction, in vitro kinase assays on stathmin/MBP/synapsin, and fractionation showing nuclear targeting\",\n      \"pmids\": [\"9287318\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vitro substrates not yet validated as physiological\", \"Functional role of the UHM/RRM domain undefined\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Defining UHMK1's preference for Ser-Pro motifs, distinct from MAP kinases and CDKs, gave it a substrate-recognition logic and a mapped phosphosite on MBP.\",\n      \"evidence\": \"In vitro kinase assay with mass spectrometry and phosphopeptide mapping\",\n      \"pmids\": [\"10880969\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Consensus determined on model substrates, not endogenous targets\", \"Regulation of autophosphorylation by histones not mechanistically explained\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identifying UHMK1 as a direct FoxM1 transcriptional target placed it within a growth-factor-driven program controlling p27Kip1 localization and cell cycle entry.\",\n      \"evidence\": \"FoxM1 deletion/siRNA, immunoblotting and promoter/reporter analysis in cells\",\n      \"pmids\": [\"17984092\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct kinase action on p27 not addressed in this study\", \"Other upstream transcriptional inputs unexplored\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Domain mapping showed the kinase domain drives nuclear localization while the UHM domain mediates SF1/SF3b155 binding, mechanistically tying UHMK1 to the spliceosome.\",\n      \"evidence\": \"Deletion/mutation localization constructs, GST pull-down and co-IP with splicing factors\",\n      \"pmids\": [\"18588901\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SF1/SF3b155 are phosphorylation substrates not established here\", \"Functional consequence for splicing not measured\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"The KIS knockout mouse established a physiological in vivo function: phosphorylation of stathmin Ser38 to limit VSMC migration and p27-dependent proliferation in vascular injury.\",\n      \"evidence\": \"KIS-/- mice in a vascular injury model with stathmin knockdown rescue (epistasis)\",\n      \"pmids\": [\"19033656\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific roles beyond vasculature not addressed\", \"Balance between stathmin and p27 arms not quantified\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Direct phosphorylation of p27Kip1 at Ser10 by UHMK1 connected its kinase activity to suppression of the G0/G1 arrest, demonstrated in leukemia cells.\",\n      \"evidence\": \"Co-IP, kinase assay, siRNA knockdown with cell cycle analysis\",\n      \"pmids\": [\"18384876\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Nuclear export step downstream of S10 not directly shown in this system\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Localization to neuronal RNA granules with KIF3A, NonO and eEF1A revealed a cytoplasmic role in mRNA transport and local translation supporting neurite outgrowth.\",\n      \"evidence\": \"Co-IP from brain extracts, colocalization imaging, knockdown and local translation reporters\",\n      \"pmids\": [\"19015237\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Granule substrate(s) phosphorylated by KIS not identified\", \"Mechanism coupling kinase activity to translation unclear\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"FRAP and substrate studies showed UHMK1 cycles rapidly between nucleus and cytosol, and cytosolic UHMK1 phosphorylates the PAM cytosolic domain to control its nuclear access and POMC processing.\",\n      \"evidence\": \"FRAP, phosphomimetic mutations, overexpression and microarray in endocrine cells\",\n      \"pmids\": [\"20573687\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"PAM phosphorylation site not mapped by mass spectrometry\", \"Direct kinase-substrate relationship inferred, not reconstituted\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Placing UHMK1-driven p27 Ser10 phosphorylation downstream of PI3K/Rac1 and ERK1/2 integrated it into FGF-2-stimulated proliferative signaling.\",\n      \"evidence\": \"siRNA, Rac1-GTP pull-down, phospho-p27 immunoblot and proliferation assays with pathway inhibitors\",\n      \"pmids\": [\"20811053\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct linkage between the kinases and UHMK1 activation not biochemically defined\", \"Single cell type\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identifying CATS/FAM64A as a Ser131 substrate and transcriptional partner extended UHMK1's influence to transcriptional repression and CALM/AF10 antagonism.\",\n      \"evidence\": \"Two-hybrid, pull-down, co-IP, in vitro kinase assay with site mapping and reporter assays\",\n      \"pmids\": [\"23419774\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional role of S131 phosphorylation unresolved (transcriptional effect was phosphorylation-independent)\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"In hippocampal neurons UHMK1 was shown to counteract CPEB3 repression of GluR2 translation, linking its kinase activity to spine development and synaptic strength.\",\n      \"evidence\": \"KIS knockdown, spine morphology, fractionation and CPEB3 epistasis/translation reporters\",\n      \"pmids\": [\"25319695\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CPEB3 is a direct UHMK1 substrate not established\", \"Molecular step relieving CPEB3 repression undefined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"A MARCKS-UHMK1 axis was placed upstream of p27 control, with kinase-dead rescue confirming UHMK1 catalytic activity as the essential effector of VSMC proliferation.\",\n      \"evidence\": \"siRNA, kinase-dead rescue, nuclear fractionation, BrdU and vascular injury model\",\n      \"pmids\": [\"26528715\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which MARCKS controls UHMK1 levels not defined\", \"Direct vs indirect MARCKS-UHMK1 link unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"The YAP/FOXM1-UHMK1-MYBL2 axis defined an oncogenic role in hepatocellular carcinoma, with UHMK1 enriching MYBL2 in the nucleus to drive cell cycle genes.\",\n      \"evidence\": \"BioID/MS, co-IP, reporter assays, nuclear fractionation and YAP-transgenic mice with HCC tissue\",\n      \"pmids\": [\"30936457\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MYBL2 is a phosphorylation substrate not shown\", \"Mechanism of MYBL2 nuclear enrichment not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Mapping NCOA3 Ser1062/Thr1067 phosphorylation linked UHMK1 to ATF4-driven de novo purine synthesis and gastric cancer progression.\",\n      \"evidence\": \"Site mutagenesis, co-IP, in vitro kinase assay, pathway-inhibitor rescue, xenografts and human tissue\",\n      \"pmids\": [\"31975428\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signals activating this axis in tumors not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"A UHMK1-STAT3 positive feedback loop was shown to support colorectal cancer proliferation and oxaliplatin resistance.\",\n      \"evidence\": \"Co-IP, knockdown/overexpression, reporter and drug-sensitivity assays\",\n      \"pmids\": [\"35501324\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of STAT3 activation not biochemically defined\", \"Whether STAT3 is a substrate unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Phosphorylation of coilin connected UHMK1 to Cajal body dynamics and 5-FU-responsive alternative splicing in colon cancer.\",\n      \"evidence\": \"Phosphorylation assay, immunofluorescence of Cajal bodies, splicing and viability assays\",\n      \"pmids\": [\"35151311\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Coilin phosphosite not mapped by mutagenesis\", \"Single study, single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Global phosphoproteomics and RNA-seq established UHMK1 as a bona fide splicing-regulatory kinase targeting spliceosome components and controlling hundreds of alternative splicing events.\",\n      \"evidence\": \"Phosphoproteomics, RNA-seq, splicing reporter and siRNA in cells\",\n      \"pmids\": [\"36803961\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect status of many putative substrates unverified\", \"Functional consequences of individual splicing changes not dissected\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Phosphorylation of PTBP2 provided a mechanistic basis for UHMK1's splicing control in neurons by dissociating PTBP2 from Matrin3/hnRNPM and reducing RNA binding during differentiation.\",\n      \"evidence\": \"In vitro kinase assay, RNA-seq, co-IP, RNA-binding assay and KIS/PTBP2 epistasis on spine maturation\",\n      \"pmids\": [\"38597390\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific phosphosites on PTBP2 not enumerated here\", \"Generality to non-neuronal PTB proteins untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"SOX4 was identified as an additional transcriptional activator of UHMK1, with UHMK1 promoting lung adenocarcinoma growth via ID1/β-catenin signaling.\",\n      \"evidence\": \"Dual luciferase, RT-qPCR, western blot, knockdown/overexpression and xenografts\",\n      \"pmids\": [\"39052126\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"ID1/β-catenin connection not mechanistically dissected; single lab, single study\", \"Direct UHMK1 substrate in this pathway unidentified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"A UHMK1-NCOA3-ATF4-MTHFD2 axis with positive feedback extended the metabolic-coactivator mechanism to one-carbon metabolism in prostate cancer.\",\n      \"evidence\": \"Co-IP, in vitro kinase assay, knockdown/overexpression and xenografts\",\n      \"pmids\": [\"40918462\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"NCOA3 phosphosite not mapped by mutagenesis in this study\", \"Single lab, single study\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"UHMK1 was shown to stabilize STMN1 against proteasomal degradation and to co-activate PI3K/AKT/mTOR signaling driving vasculogenic mimicry in oral squamous cell carcinoma.\",\n      \"evidence\": \"Co-IP, ubiquitination/proteasome-inhibitor assay, knockdown, VM assay and IHC\",\n      \"pmids\": [\"41966283\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitination sites and whether stabilization requires kinase activity not established\", \"Reconciliation with prior stathmin-degradation role unaddressed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How UHMK1 dynamically partitions between its nuclear cell-cycle/splicing functions and cytoplasmic RNA-granule/translation functions, and what governs substrate selection across these compartments, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model linking UHM-domain docking to substrate phosphorylation\", \"Signals controlling nucleocytoplasmic cycling not defined\", \"Direct vs indirect status of many proposed substrates unverified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 4, 6, 9, 13, 17]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 1, 6, 13, 17]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 3, 5]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 4, 20]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 3, 7]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [2, 6, 8, 12]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [3, 16, 17]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [9, 12, 13]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [12, 13, 14]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [8, 11, 14, 20]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"STMN1\", \"CDKN1B\", \"SF1\", \"SF3B1\", \"PTBP2\", \"FAM64A\", \"MYBL2\", \"NCOA3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":8,"faith_total":8,"faith_pct":100.0}}