Affinage

KHDRBS1

KH domain-containing, RNA-binding, signal transduction-associated protein 1 · UniProt Q07666

Round 2 corrected
Length
443 aa
Mass
48.2 kDa
Annotated
2026-04-28
130 papers in source corpus 21 papers cited in narrative 21 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KHDRBS1 (Sam68) is a STAR-family KH-domain RNA-binding protein that functions as a signal-regulated nexus linking tyrosine- and MAP-kinase cascades to post-transcriptional gene control, DNA damage responses, and metabolic homeostasis. It binds UAAA-rich RNA motifs through a composite KH/STAR domain and acts as a signal-dependent alternative splicing regulator: ERK phosphorylation stimulates CD44 v5 exon inclusion, Fyn-mediated tyrosine phosphorylation shifts Bcl-x splicing toward the anti-apoptotic Bcl-x(L) isoform, and loss of Sam68 causes mTOR intron 5 retention that impairs adipogenesis in vivo (PMID:12478298, PMID:17371836, PMID:22424772). Beyond splicing, Sam68 facilitates PARP1-dependent poly(ADP-ribose) synthesis at DNA lesions, stabilizes CRTC2 to promote hepatic gluconeogenesis, and is required for HIV-1 Rev/RRE-dependent mRNA nuclear export (PMID:27635653, PMID:34099657, PMID:15701759). Missense variants in KHDRBS1 cause splicing defects linked to primary ovarian insufficiency, and Sam68-null female mice exhibit subfertility due to impaired gonadotropin receptor mRNA accumulation (PMID:28938739, PMID:20881015).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1994 High

    The identification of Sam68 as a mitotic Src-kinase substrate that independently binds RNA established the founding paradigm of a signaling-responsive RNA-binding protein.

    Evidence In vitro SH2/SH3 pulldowns and co-IP with tyrosine phosphorylation assays in mouse fibroblasts

    PMID:7512694

    Open questions at the time
    • Physiological RNA targets unknown
    • In vivo consequence of Src phosphorylation on RNA binding not tested
    • No information on downstream RNA processing events
  2. 1997 High

    Defining the UAAA-binding specificity and requirement for the full KH-STAR domain (not KH alone) resolved how Sam68 recognizes RNA and linked it functionally to the GLD-1/FMR1 STAR family.

    Evidence In vitro SELEX, filter-binding Kd measurements, and KH-domain deletion/point mutagenesis

    PMID:9341174

    Open questions at the time
    • In vivo target repertoire undefined
    • Structural basis of extended KH-STAR recognition unknown
    • Whether additional co-factors modulate specificity not addressed
  3. 2002 High

    Demonstration that ERK directly phosphorylates Sam68 to drive CD44 v5 exon inclusion established Sam68 as the first signal-regulated alternative splicing factor coupling Ras-MAPK signaling to splice-site selection.

    Evidence In vitro splicing reconstitution with ERK-phosphorylated Sam68, phospho-site mutagenesis, and antisense suppression of endogenous Sam68

    PMID:12478298

    Open questions at the time
    • Full set of ERK phosphorylation sites not mapped
    • Whether other Ras-pathway effectors contribute in parallel unclear
    • Genome-wide scope of ERK-Sam68-dependent splicing unknown
  4. 2002 Medium

    Identification of endogenous mRNA targets (hnRNP A2/B1, β-actin) and the RNA-independent interaction with hnRNP K broadened Sam68's functional scope to mRNA metabolism and nuclear export regulation via RRE.

    Evidence Co-IP of endogenous mRNAs, in vitro binding assays, RRE reporter assays, and RNase-resistant Sam68–hnRNP K pulldown

    PMID:12370808 PMID:12490714

    Open questions at the time
    • Transcriptome-wide target catalog incomplete
    • Functional impact on hnRNP A2/B1 mRNA fate not determined
    • Physiological relevance of hnRNP K–Sam68 complex unclear
  5. 2005 Medium

    Stable Sam68 knockdown blocking HIV-1 Rev/RRE-mediated RNA export (~1000-fold titer reduction) and the discovery of Brm–Sam68 coupling transcription elongation to splicing established two new mechanistic axes: nuclear RNA export co-factor and co-transcriptional splicing facilitator.

    Evidence Stable RNAi, nuclear/cytoplasmic RNA fractionation, viral titer measurement; co-IP of Brm with Sam68 and spliceosomal components, ChIP for RNAPII on CD44

    PMID:15701759 PMID:16341228

    Open questions at the time
    • Identity of Sam68–Rev bridging factor not resolved
    • Whether Brm interaction is direct or through an RNA intermediate not established
    • Generality of Brm–Sam68 mechanism beyond CD44 untested
  6. 2007 High

    The finding that Sam68 shifts Bcl-x splicing toward the pro-apoptotic Bcl-x(s) isoform, reversible by Fyn-mediated tyrosine phosphorylation, provided the first example of kinase-toggled apoptotic splicing control.

    Evidence RNAi, overexpression, Fyn phosphorylation mutants, co-IP with hnRNP A1, RT-PCR splicing assays

    PMID:17371836

    Open questions at the time
    • Precise Fyn phospho-sites mediating splice-switch not mapped
    • Structural basis for phosphorylation-dependent hnRNP A1 release unknown
    • In vivo apoptotic consequence in tissues not tested
  7. 2010 High

    Sam68-knockout female mice revealed an essential in vivo role in female fertility: Sam68 directly binds Fshr and Lhcgr mRNAs (by CLIP) and is required for gonadotropin receptor mRNA accumulation during folliculogenesis.

    Evidence Sam68 KO mice, CLIP, RT-PCR/Western blot in ovarian tissue, FSH/cAMP stimulation

    PMID:20881015

    Open questions at the time
    • Whether Sam68 stabilizes or promotes biogenesis of receptor mRNAs not distinguished
    • Male fertility phenotype mechanism not detailed here
    • Downstream signaling consequences in follicle cells not fully characterized
  8. 2012 High

    Discovery that Sam68-null mice are lean due to mTOR intron-5 retention—reducing mTOR protein and S6K/Akt signaling—established Sam68 as a physiologically essential splicing regulator of a central metabolic kinase.

    Evidence KO mice, genome-wide exon-array profiling, RT-PCR, immunoprecipitation, rescue with exogenous mTOR

    PMID:22424772

    Open questions at the time
    • Whether Sam68 directly contacts mTOR intron-5 splice elements awaits CLIP at the mTOR locus
    • Tissue specificity of this splicing event beyond adipocytes not fully explored
    • Possible additional splicing targets contributing to lean phenotype
  9. 2016 High

    The demonstration that Sam68 is recruited to DNA lesions and required for PARP1-dependent PAR synthesis unveiled a non-RNA function in the DNA damage response, explaining genotoxin hypersensitivity of Sam68-null cells and mice.

    Evidence KO mice/cells, co-IP with PARP1, laser microirradiation live-cell imaging, quantitative PAR measurement

    PMID:27635653

    Open questions at the time
    • Whether Sam68 stimulates PARP1 catalytic activity directly or via structural scaffolding unclear
    • Role of Sam68 RNA-binding domain in DNA-damage context not resolved
    • Interplay between Sam68 splicing and DDR functions at DNA lesions unknown
  10. 2017 Medium

    Identification of KHDRBS1 missense variants (p.M154V, p.P88L) in patients with primary ovarian insufficiency, causing transcriptome-wide splicing defects enriched in DNA repair genes, provided a direct genetic link between Sam68 loss-of-function and human disease.

    Evidence Whole-exome sequencing of POI patients, RNA-seq of KGN cells expressing mutant KHDRBS1

    PMID:28938739

    Open questions at the time
    • Variant functional impact not tested by in vitro splicing reconstitution
    • Small patient cohort limits genotype-phenotype correlation
    • Whether POI mechanism is primarily through DDR or folliculogenesis pathway unclear
  11. 2020 Medium

    Sam68 binding to Alu-element-rich intronic sequences in the SMN locus to promote circRNA biogenesis extended Sam68's RNA-processing repertoire to back-splicing and circular RNA generation.

    Evidence CLIP, mutagenesis of binding sites, siRNA knockdown, RT-PCR for circRNAs

    PMID:31777926

    Open questions at the time
    • Genome-wide scope of Sam68-dependent circRNA biogenesis not determined
    • Functional consequence of SMN circRNAs unknown
    • Whether Alu-binding generalizes to other STAR-family proteins untested
  12. 2021 High

    Sam68 stabilizes CRTC2 by reducing its ubiquitination, thereby driving hepatic gluconeogenesis—a non-RNA-binding function with direct metabolic consequences confirmed by liver-specific KO and domain-truncation transgenic mice.

    Evidence Global and liver-specific KO mice, domain truncation transgenics, co-IP, ubiquitination assays, blood glucose measurements

    PMID:34099657

    Open questions at the time
    • E3 ligase antagonized by Sam68 not identified
    • Whether Sam68 directly blocks ubiquitin transfer or recruits a DUB unknown
    • Relative contribution of splicing vs. CRTC2-stabilization functions to metabolic phenotype unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major open questions include the structural basis of the KH-STAR domain's extended RNA recognition, whether RNA-binding and non-RNA adaptor functions are regulated by the same or distinct phosphorylation events, and the integrative logic by which a single protein coordinates alternative splicing, circRNA biogenesis, PARP1 activation, and protein stabilization across tissues.
  • No high-resolution structure of Sam68 KH-STAR domain bound to RNA
  • Phosphorylation code governing functional switching not systematically defined
  • Tissue-specific interactome not mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 7 GO:0140098 catalytic activity, acting on RNA 4 GO:0060090 molecular adaptor activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005634 nucleus 6 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-8953854 Metabolism of RNA 4 R-HSA-5357801 Programmed Cell Death 3 R-HSA-1430728 Metabolism 2 R-HSA-1474165 Reproduction 2 R-HSA-1643685 Disease 2 R-HSA-73894 DNA Repair 1
Partners
CRTC2FYNHNRNPA1HNRNPKPARP1RELASMARCA2SRC

Evidence

Reading pass · 21 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 KHDRBS1/Sam68 (p68) was identified as a substrate of c-Src tyrosine kinase during mitosis. Sam68 independently binds the Src SH2 and SH3 domains in vitro, and both domains are required for Sam68 phosphorylation and association in vivo. Sam68 also selectively binds polyribonucleotides, linking c-Src signaling to potential RNA regulatory functions. In vitro binding assays (SH2/SH3 domain pulldowns), in vivo co-immunoprecipitation, tyrosine phosphorylation assays in mitotic mouse fibroblasts Nature High 7512694
1997 Sam68 binds RNA with high specificity and affinity through a region encompassing the KH domain plus an adjacent region conserved in the Sam68 subgroup (STAR family). The KH domain alone is insufficient for RNA binding; deletion of the KH domain or KH mutations analogous to loss-of-function mutations in FMR1 and GLD-1 abolished binding. The highest-affinity RNA motif recognized by Sam68 is UAAA. In vitro SELEX RNA selection, filter-binding affinity assays (Kd measurement), deletion mutagenesis of Sam68, site-directed mutagenesis of KH domain residues The Journal of biological chemistry High 9341174
2002 Sam68 regulates alternative splicing of the CD44 v5 exon downstream of the Ras/ERK signaling pathway. Sam68 is a direct substrate of ERK; ERK phosphorylation of Sam68 at multiple sites stimulates v5-exon inclusion in vitro. Suppression of Sam68 expression abolished Ras-pathway-induced alternative splicing of endogenous CD44-v5. In vitro splicing assays with ERK-phosphorylated Sam68, ERK phosphorylation site mutagenesis, Sam68 antisense suppression in cells, forced Sam68 expression, endogenous CD44-v5 splicing assays Nature High 12478298
2002 Sam68 binds cellular mRNAs including hnRNP A2/B1 and beta-actin mRNAs in vivo in an RNA-binding-domain-dependent manner. Sam68 recognizes UAAA motifs and poly(U) sequences within loop structures for in vivo mRNA binding. Differential display and cDNA-representational difference analysis; RT-PCR of RNAs co-immunoprecipitated with Sam68; in vitro binding assays; RNA-binding domain mutation Nucleic acids research Medium 12490714
2002 Sam68 physically interacts with hnRNP K both in vitro and in vivo. This interaction does not require RNA (RNase-resistant), and hnRNP K forms a super-complex with Sam68 and RRE-RNA in vitro. hnRNP K inhibits Sam68-mediated, but not Rev-mediated, RRE-dependent gene expression, and Sam68 inhibits hnRNP K-mediated transcriptional activation. In vitro pulldown and co-immunoprecipitation, RNase treatment, RRE-reporter gene assays, transcription activation assays Oncogene Medium 12370808
2004 Conditional overexpression of Sam68 in fibroblasts causes both G1-phase cell cycle arrest and apoptosis via separable mechanisms. G1 arrest is associated with decreased cyclin D1 and E RNA/protein and reduced Rb phosphorylation, and does not require Sam68's RNA-binding activity. Apoptosis induction, by contrast, absolutely requires a functional RNA-binding domain. Conditional Sam68 overexpression system, RNA-binding domain point mutants, flow cytometry, Western blotting for cyclins and Rb phosphorylation BMC cell biology Medium 14736338
2005 Sam68 is required for HIV-1 Rev-mediated RNA export and virus production. Stable Sam68 knockdown (SSKH cells) blocked Rev-mediated RRE reporter gene expression, inhibited nuclear export of RRE-containing mRNAs, and reduced HIV-1 titers ~1000-fold. Sam68 interacts with the IRES in the FMDV 5' NTR and its knockdown decreases FMDV IRES-driven activity. RNAi-mediated stable knockdown, CAT/gag reporter assays, nuclear/cytoplasmic RNA fractionation, viral titer measurement Nucleic acids research Medium 15701759
2005 Sam68 participates in signal transduction as an adaptor protein: it contains proline-rich sequences for SH3 domain binding, and C-terminal tyrosine-rich regions phosphorylated by tyrosine kinases (Src, ZAP-70, leptin receptor, insulin receptor), enabling recruitment to SH2-containing signaling complexes. Tyrosine phosphorylation of Sam68 negatively regulates its RNA-binding activity. Co-immunoprecipitation, in vitro tyrosine phosphorylation assays, domain interaction assays with SH2/SH3 domain proteins Cellular and molecular life sciences Medium 15619005
2005 The chromatin-remodeling ATPase Brm (SWI/SNF subunit) associates with Sam68 and components of the spliceosome. Brm induces RNA polymerase II accumulation with modified CTD phosphorylation at variant exon regions of CD44, and Brm–Sam68 interaction facilitates recruitment of the splicing machinery to exons with suboptimal splice sites, coupling transcription elongation rate to alternative splicing. Co-immunoprecipitation of Brm with Sam68 and spliceosomal components, ChIP for RNAPII on CD44 gene, splicing reporter assays Nature structural & molecular biology Medium 16341228
2007 Sam68 binds the Bcl-x pre-mRNA and regulates its alternative splicing. Sam68 depletion by RNAi promotes antiapoptotic Bcl-x(L) isoform accumulation, while Sam68 overexpression increases proapoptotic Bcl-x(s). Tyrosine phosphorylation of Sam68 by Fyn kinase reverses this effect and favors Bcl-x(L) splice site selection. Sam68 interacts with hnRNP A1, and disruption of this interaction attenuates Bcl-x(s) splicing. An RS domain or ASF/SF2 co-expression can counteract Sam68's proapoptotic splicing activity. RNAi knockdown, Sam68 overexpression, Fyn kinase phosphorylation (point mutants), co-immunoprecipitation with hnRNP A1, RS domain fusion constructs, RT-PCR splicing assays The Journal of cell biology High 17371836
2010 Sam68 ablation in female mice causes subfertility, with reduced secondary and pre-antral follicle numbers and impaired gonadotropin-dependent follicle development. Sam68 directly binds the mRNAs for FSH receptor (Fshr) and LH receptor (Lhcgr) as shown by crosslinking/immunoprecipitation, and these transcripts are downregulated in Sam68-null ovaries. FSH or its second messenger (8Br-cAMP) upregulates Sam68, which is required for accumulation of gonadotropin receptor mRNAs in pre-ovulatory follicles. Sam68 knockout mice, CLIP (crosslinking/immunoprecipitation) experiments, RT-PCR and Western blotting, cAMP stimulation experiments, exogenous gonadotropin rescue Human molecular genetics High 20881015
2010 Sam68 overexpression in breast cancer cells is associated with promotion of G1-to-S phase transition. Sam68 knockdown by siRNA inhibits cell proliferation and tumorigenicity by upregulating p21(Cip1) and p27(Kip1), enhancing FOXO factor transactivation, and attenuating Akt/GSK-3β signaling. siRNA knockdown of endogenous Sam68, cell proliferation assays, flow cytometry, Western blotting for cell cycle regulators, Akt/GSK-3β phosphorylation assays, immunohistochemistry The Journal of pathology Medium 20662004
2011 Hsp22 (HspB8) inversely regulates Sam68 expression. Hsp22 knockdown in U87 glioblastoma cells dramatically increases both Sam68 mRNA and protein levels, alters cell morphology, and enhances proliferation associated with increased cyclin E, cyclin A, RNR, and PCNA expression and G1-to-S phase transition. siRNA knockdown of Hsp22, Western blotting, RT-PCR, flow cytometry cell cycle analysis, proliferation assays Journal of cellular physiology Low 21678403
2012 Sam68 regulates mTOR alternative splicing during adipogenesis. Sam68-null mice exhibit a lean phenotype with increased energy expenditure and defective adipogenesis. In Sam68-null adipocytes, intron 5 of mTOR is retained, introducing a premature stop codon and reducing mTOR protein levels, leading to reduced S6 and Akt phosphorylation. Sam68 binds intronic splice elements within mTOR intron 5 required for 5' splice site usage. The adipogenesis defect is rescued by exogenous full-length mTOR. Sam68 knockout mice, genome-wide exon usage profiling (microarray), RT-PCR, immunoprecipitation, Western blotting for mTOR/S6/Akt, rescue with exogenous mTOR expression Molecular cell High 22424772
2012 FMDV 3C protease cleaves the C-terminus of nuclear Sam68 (which contains the nuclear localization sequence), causing Sam68 redistribution to the cytoplasm during FMDV infection. Sam68 knockdown reduced viral titers ~1000-fold. Sam68 interacts with the IRES in the FMDV 5' non-translated region, and Sam68 knockdown decreased FMDV IRES-driven translation activity in vitro. Viral infection assays, siRNA knockdown, cellular fractionation, co-immunoprecipitation of Sam68 with FMDV IRES RNA, viral titer measurement, IRES reporter assays Virology Medium 22280896
2015 Sam68 promotes NF-κB signaling activation and apoptosis in TNF-α-stimulated articular chondrocytes. Sam68 knockdown suppresses IκB degradation and p65 nuclear translocation. Upon TNF-α exposure, Sam68 translocates to the nucleus and physically interacts with the NF-κB subunit p65 as shown by co-immunoprecipitation. siRNA knockdown of Sam68, co-immunoprecipitation of Sam68 with p65, nuclear/cytoplasmic fractionation Western blotting, apoptosis markers (cleaved caspase-3, PARP), immunoblotting for catabolic genes Inflammation research Medium 26350037
2016 Sam68 is required for DNA damage responses by facilitating PARP1-mediated poly(ADP-ribose) (PAR) synthesis. Sam68 is recruited to DNA lesions and co-localizes with PARP1 at sites of damage. The Sam68–PARP1 interaction is required for robust PAR production upon DNA damage. Sam68-knockout cells and mice are hypersensitive to DNA-damaging agents, and PAR-dependent DNA repair signaling is dramatically diminished in Sam68-null cells. Sam68 KO cells and mice, co-immunoprecipitation of Sam68 with PARP1, laser microirradiation/live-cell imaging of Sam68 recruitment to DNA damage foci, PAR chain measurement, genotoxicity sensitivity assays PLoS biology High 27635653
2017 KHDRBS1 variants (p.M154V and p.P88L) identified in patients with primary ovarian insufficiency (POI) cause defects in mRNA alternative splicing. RNA-sequencing revealed that cells expressing M154V KHDRBS1 have 145 alternatively spliced genes enriched for DNA replication and repair functions, consistent with a mechanism underlying POI pathology. Whole-exome sequencing, Sanger sequencing, RNA-sequencing of KGN cells expressing mutant vs. wild-type KHDRBS1, bioinformatics analysis of alternative splicing events Human reproduction Medium 28938739
2018 The lncRNA CYTOR interacts directly with Sam68 (KHDRBS1) and NCL, forming a heterotrimeric complex. EXON1 of CYTOR contains specific binding motifs recognized by both NCL and Sam68, and this complex activates the NF-κB pathway and promotes EMT to drive colorectal cancer progression. ChIRP-MS (chromatin isolation by RNA purification coupled to mass spectrometry), RNA immunoprecipitation (RIP), CRISPR/Cas9 mutagenesis of CYTOR binding sites, luciferase reporter assays for NF-κB, knockdown/overexpression functional assays Molecular cancer Medium 30064438
2020 Sam68 binds Alu-rich intronic sequences in the SMN pre-mRNA via ultra-conserved binding sites identified by bioinformatics. CLIP and mutagenesis experiments show Sam68 binds in proximity to inverted repeat Alu elements (IRAlus) in SMN introns. Sam68 promotes circRNA biogenesis from the SMN locus in vitro and in vivo; Sam68 silencing reduces SMN circRNA production. CLIP (crosslinking/immunoprecipitation), mutagenesis of Sam68 binding sites, Sam68 siRNA silencing, RT-PCR for circRNA detection, bioinformatics analysis of Alu density Nucleic acids research Medium 31777926
2021 Sam68 promotes hepatic gluconeogenesis by stabilizing CRTC2, a key transcriptional co-activator of gluconeogenic genes. Sam68 physically interacts with CRTC2 and reduces CRTC2 ubiquitination. Sam68 truncation mutants lacking either the C-terminal (Sam68ΔC, fails to bind CRTC2) or N-terminal domain (Sam68ΔN, fails to stabilize CRTC2) confirm domain requirements. Sam68ΔN transgenic mice recapitulate the hypoglycemic phenotype of Sam68-null mice. Hepatic Sam68 is upregulated in diabetic patients and mouse models. Global and liver-specific Sam68 KO mice, Sam68 domain truncation mutants and transgenic mice, co-immunoprecipitation of Sam68 with CRTC2, ubiquitination assays, blood glucose measurement, gluconeogenic gene expression, diabetic mouse model rescue Nature communications High 34099657

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell 2861 17081983
2012 Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell 1718 22658674
2005 A human protein-protein interaction network: a resource for annotating the proteome. Cell 1704 16169070
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2009 Monitoring autophagic degradation of p62/SQSTM1. Methods in enzymology 991 19200883
2012 The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts. Molecular cell 973 22681889
2013 Phosphorylation of p62 activates the Keap1-Nrf2 pathway during selective autophagy. Molecular cell 969 24011591
2009 p62 at the crossroads of autophagy, apoptosis, and cancer. Cell 938 19524504
2005 Nucleolar proteome dynamics. Nature 934 15635413
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2008 Global analysis of host-pathogen interactions that regulate early-stage HIV-1 replication. Cell 787 18854154
2016 p62 links the autophagy pathway and the ubiqutin-proteasome system upon ubiquitinated protein degradation. Cellular & molecular biology letters 757 28536631
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2015 p62/SQSTM1 functions as a signaling hub and an autophagy adaptor. The FEBS journal 669 26432171
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2018 High-Density Proximity Mapping Reveals the Subcellular Organization of mRNA-Associated Granules and Bodies. Molecular cell 580 29395067
2015 p62 links autophagy and Nrf2 signaling. Free radical biology & medicine 535 26117325
2017 Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15. Science (New York, N.Y.) 533 28302793
1999 TRANCE, a TNF family member, activates Akt/PKB through a signaling complex involving TRAF6 and c-Src. Molecular cell 502 10635328
2008 The signaling adaptor p62 is an important NF-kappaB mediator in tumorigenesis. Cancer cell 474 18394557
2010 Physiological significance of selective degradation of p62 by autophagy. FEBS letters 445 20153326
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2011 p62 is a key regulator of nutrient sensing in the mTORC1 pathway. Molecular cell 421 21981924
2013 The intracellular interactome of tetraspanin-enriched microdomains reveals their function as sorting machineries toward exosomes. The Journal of biological chemistry 413 23463506
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
1994 An RNA-binding protein associated with Src through its SH2 and SH3 domains in mitosis. Nature 391 7512694
2002 Signal-dependent regulation of splicing via phosphorylation of Sam68. Nature 383 12478298
2005 The human SWI/SNF subunit Brm is a regulator of alternative splicing. Nature structural & molecular biology 379 16341228
2007 Systematic analysis of the protein interaction network for the human transcription machinery reveals the identity of the 7SK capping enzyme. Molecular cell 367 17643375
2004 Identifying and quantifying in vivo methylation sites by heavy methyl SILAC. Nature methods 364 15782174
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2010 Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics. Cell 318 21145461
2018 p62 filaments capture and present ubiquitinated cargos for autophagy. The EMBO journal 297 29343546
2006 Signal integration and diversification through the p62 scaffold protein. Trends in biochemical sciences 278 17174552
2007 The RNA-binding protein Sam68 modulates the alternative splicing of Bcl-x. The Journal of cell biology 270 17371836
2006 p62/SQSTM1: a missing link between protein aggregates and the autophagy machinery. Autophagy 266 16874037
2012 p62/SQSTM1/A170: physiology and pathology. Pharmacological research 254 22841931
2018 p62/SQSTM1 - steering the cell through health and disease. Journal of cell science 232 30397181
2010 Selective degradation of p62 by autophagy. Seminars in immunopathology 212 20814791
2018 p62/SQSTM1: 'Jack of all trades' in health and cancer. The FEBS journal 206 30499183
2018 Autophagic Regulation of p62 is Critical for Cancer Therapy. International journal of molecular sciences 205 29738493
2016 TRIM21 Ubiquitylates SQSTM1/p62 and Suppresses Protein Sequestration to Regulate Redox Homeostasis. Molecular cell 191 26942676
2011 Autophagy and p62 in cardiac proteinopathy. Circulation research 163 21659648
2018 Oxidation of SQSTM1/p62 mediates the link between redox state and protein homeostasis. Nature communications 154 29343728
2019 SQSTM1/p62 and PPARGC1A/PGC-1alpha at the interface of autophagy and vascular senescence. Autophagy 152 31441382
2012 p62 at the interface of autophagy, oxidative stress signaling, and cancer. Antioxidants & redox signaling 151 22074114
1997 Specificity and determinants of Sam68 RNA binding. Implications for the biological function of K homology domains. The Journal of biological chemistry 150 9341174
2019 SQSTM1/p62 promotes mitochondrial ubiquitination independently of PINK1 and PRKN/parkin in mitophagy. Autophagy 142 31339428
2006 Sequestosome 1/p62--more than just a scaffold. FEBS letters 140 17188686
2008 Hypoxia-activated autophagy accelerates degradation of SQSTM1/p62. Oncogene 137 18931699
2011 The RNA-binding protein Sam68 is a multifunctional player in human cancer. Endocrine-related cancer 136 21565971
2019 Requirement for p62 acetylation in the aggregation of ubiquitylated proteins under nutrient stress. Nature communications 131 31857589
2013 Interaction domains of p62: a bridge between p62 and selective autophagy. DNA and cell biology 128 23530606
2016 SQSTM1/p62 mediates crosstalk between autophagy and the UPS in DNA repair. Autophagy 127 27391408
2019 p62/SQSTM1 and Selective Autophagy in Cardiometabolic Diseases. Antioxidants & redox signaling 123 30588824
1998 P62 and the sequestosome, a novel mechanism for protein metabolism. Archives of pharmacal research 121 9868528
2013 Role of p62/SQSTM1 in liver physiology and pathogenesis. Experimental biology and medicine (Maywood, N.J.) 119 23856904
2018 The long non-coding RNA CYTOR drives colorectal cancer progression by interacting with NCL and Sam68. Molecular cancer 118 30064438
2017 Keap1/Cullin3 Modulates p62/SQSTM1 Activity via UBA Domain Ubiquitination. Cell reports 116 28380357
2014 P62/SQSTM1 at the interface of aging, autophagy, and disease. Age (Dordrecht, Netherlands) 116 24557832
2020 NBR1-mediated p62-liquid droplets enhance the Keap1-Nrf2 system. EMBO reports 105 31916398
2017 From autophagy to mitophagy: the roles of P62 in neurodegenerative diseases. Journal of bioenergetics and biomembranes 104 28975445
2012 The Sam68 STAR RNA-binding protein regulates mTOR alternative splicing during adipogenesis. Molecular cell 95 22424772
2020 The Calcineurin-TFEB-p62 Pathway Mediates the Activation of Cardiac Macroautophagy by Proteasomal Malfunction. Circulation research 94 32366200
2018 Rapid induction of p62 and GABARAPL1 upon proteasome inhibition promotes survival before autophagy activation. The Journal of cell biology 92 29535191
2018 ZZ-dependent regulation of p62/SQSTM1 in autophagy. Nature communications 90 30349045
2010 Sam68 up-regulation correlates with, and its down-regulation inhibits, proliferation and tumourigenicity of breast cancer cells. The Journal of pathology 89 20662004
2021 LSD1-Demethylated LINC01134 Confers Oxaliplatin Resistance Through SP1-Induced p62 Transcription in HCC. Hepatology (Baltimore, Md.) 87 34322883
2021 The Pathways Underlying the Multiple Roles of p62 in Inflammation and Cancer. Biomedicines 83 34206503
2015 SAM68: Signal Transduction and RNA Metabolism in Human Cancer. BioMed research international 81 26273626
2023 S-acylation of p62 promotes p62 droplet recruitment into autophagosomes in mammalian autophagy. Molecular cell 79 37802024
2012 The nuclear protein Sam68 is cleaved by the FMDV 3C protease redistributing Sam68 to the cytoplasm during FMDV infection of host cells. Virology 74 22280896
2018 CALCOCO2/NDP52 and SQSTM1/p62 differentially regulate coxsackievirus B3 propagation. Cell death and differentiation 68 30154446
2016 Reversal of intramyocellular lipid accumulation by lipophagy and a p62-mediated pathway. Cell death discovery 66 27625792
2004 Sam68 exerts separable effects on cell cycle progression and apoptosis. BMC cell biology 64 14736338
2014 The adaptor protein p62 is involved in RANKL-induced autophagy and osteoclastogenesis. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 63 25163928
2022 OTUD7B deubiquitinates SQSTM1/p62 and promotes IRF3 degradation to regulate antiviral immunity. Autophagy 62 35100065
2017 VPS34 stimulation of p62 phosphorylation for cancer progression. Oncogene 62 28846113
2017 The BEACH-containing protein WDR81 coordinates p62 and LC3C to promote aggrephagy. The Journal of cell biology 61 28404643
2002 Identification of cellular mRNA targets for RNA-binding protein Sam68. Nucleic acids research 60 12490714
2005 Sam68 is absolutely required for Rev function and HIV-1 production. Nucleic acids research 58 15701759
2020 Sam68 binds Alu-rich introns in SMN and promotes pre-mRNA circularization. Nucleic acids research 56 31777926
2005 Role of Sam68 as an adaptor protein in signal transduction. Cellular and molecular life sciences : CMLS 55 15619005
2019 Sequestosome-1 (p62) expression reveals chaperone-assisted selective autophagy in immune-mediated necrotizing myopathies. Brain pathology (Zurich, Switzerland) 54 31376301
2022 p62 bodies: Phase separation, NRF2 activation, and selective autophagic degradation. IUBMB life 51 36331376
2013 Role of Sam68 in post-transcriptional gene regulation. International journal of molecular sciences 50 24287914
2013 TRAF6-mediated ubiquitination of NEMO requires p62/sequestosome-1. Molecular immunology 47 24270048
2021 TRIM44 links the UPS to SQSTM1/p62-dependent aggrephagy and removing misfolded proteins. Autophagy 44 34382902
2018 Role of p62 in the regulation of cell death induction. Apoptosis : an international journal on programmed cell death 44 29480462
2021 Curcumin activates Nrf2 through PKCδ-mediated p62 phosphorylation at Ser351. Scientific reports 43 33875681
2021 Sirt1 deacetylates and stabilizes p62 to promote hepato-carcinogenesis. Cell death & disease 42 33854041
2020 p62: Friend or Foe? Evidences for OncoJanus and NeuroJanus Roles. International journal of molecular sciences 41 32708719
2018 Metabolic reprogramming of the tumor microenvironment by p62 and its partners. Biochimica et biophysica acta. Reviews on cancer 41 29702207
2023 Local membrane source gathering by p62 body drives autophagosome formation. Nature communications 39 37957156
2010 Ablation of the Sam68 gene impairs female fertility and gonadotropin-dependent follicle development. Human molecular genetics 39 20881015
2009 AMPA receptor trafficking and synaptic plasticity require SQSTM1/p62. Hippocampus 38 19004011
2024 A p62-dependent rheostat dictates micronuclei catastrophe and chromosome rearrangements. Science (New York, N.Y.) 36 39208097
2019 The Multifunctional Protein p62 and Its Mechanistic Roles in Cancers. Current cancer drug targets 36 30332964
2014 Lipopolysaccharide stimulates p62-dependent autophagy-like aggregate clearance in hepatocytes. BioMed research international 36 24683544
2019 TAK1 converts Sequestosome 1/p62 from an autophagy receptor to a signaling platform. EMBO reports 35 31347268
2011 Hsp22 (HspB8/H11) knockdown induces Sam68 expression and stimulates proliferation of glioblastoma cells. Journal of cellular physiology 35 21678403
2020 Autophagic receptor p62 protects against glycation-derived toxicity and enhances viability. Aging cell 34 33146912
2021 FIP200 controls the TBK1 activation threshold at SQSTM1/p62-positive condensates. Scientific reports 33 34226595
2016 Regulation of glucose metabolism by p62/SQSTM1 through HIF1α. Journal of cell science 32 26743088
2016 Sam68 Is Required for DNA Damage Responses via Regulating Poly(ADP-ribosyl)ation. PLoS biology 32 27635653
2002 Functional interaction of Sam68 and heterogeneous nuclear ribonucleoprotein K. Oncogene 32 12370808
2015 Sam68 Promotes NF-κB Activation and Apoptosis Signaling in Articular Chondrocytes during Osteoarthritis. Inflammation research : official journal of the European Histamine Research Society ... [et al.] 30 26350037
2020 Leptin, Adiponectin, and Sam68 in Bone Metastasis from Breast Cancer. International journal of molecular sciences 29 32033341
2019 G3BP1 inhibits ubiquitinated protein aggregations induced by p62 and USP10. Scientific reports 28 31501480
2017 GBP3 promotes glioma cell proliferation via SQSTM1/p62-ERK1/2 axis. Biochemical and biophysical research communications 28 29128363
2025 Phase separation of p62: roles and regulations in autophagy. Trends in cell biology 27 40011090
2020 The scaffold protein p62 regulates adaptive thermogenesis through ATF2 nuclear target activation. Nature communications 27 32385399
2017 Sequence variants of KHDRBS1 as high penetrance susceptibility risks for primary ovarian insufficiency by mis-regulating mRNA alternative splicing. Human reproduction (Oxford, England) 27 28938739
2017 Autophagy regulates DNA repair through SQSTM1/p62. Autophagy 25 28650265
2023 Enhanced liquidity of p62 droplets mediated by Smurf1 links Nrf2 activation and autophagy. Cell & bioscience 23 36810259
2021 Sam68 promotes hepatic gluconeogenesis via CRTC2. Nature communications 23 34099657
2019 iNOS Interacts with Autophagy Receptor p62 and is Degraded by Autophagy in Macrophages. Cells 23 31618870
2022 Vault RNA1-1 riboregulates the autophagic function of p62 by binding to lysine 7 and arginine 21, both of which are critical for p62 oligomerization. RNA (New York, N.Y.) 22 35210358
2007 Targeting the RNA-binding protein Sam68 as a treatment for cancer? Future oncology (London, England) 22 17927519
2024 Targeting p62 by sulforaphane promotes autolysosomal degradation of SLC7A11, inducing ferroptosis for osteosarcoma treatment. Redox biology 21 39657365
2020 Pathogenesis of Human Papillomaviruses Requires the ATR/p62 Autophagy-Related Pathway. mBio 21 32788179
2024 PRRSV degrades MDA5 via dual autophagy receptors P62 and CCT2 to evade antiviral innate immunity. Virologica Sinica 20 38272236
2022 Acetylation of p62 regulates base excision repair through interaction with APE1. Cell reports 20 35858573
2019 A comprehensive study on genome-wide coexpression network of KHDRBS1/Sam68 reveals its cancer and patient-specific association. Scientific reports 20 31366900