Affinage

SH3RF1

E3 ubiquitin-protein ligase SH3RF1 · UniProt Q7Z6J0

Length
888 aa
Mass
93.1 kDa
Annotated
2026-06-10
48 papers in source corpus 32 papers cited in narrative 32 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SH3RF1 (POSH) is a multidomain Rac1-effector scaffold and RING-finger E3 ubiquitin ligase that couples Rho-GTPase signaling to JNK-dependent apoptosis, actin remodeling, and substrate ubiquitination across neuronal, immune, and developmental contexts (PMID:9482736, PMID:12514131). Identified as a direct effector of activated Rac, POSH nucleates a multiprotein JNK apoptotic complex by binding GTP-Rac1 together with mixed-lineage kinases, MKK4/7, and JNKs, an assembly that drives c-Jun phosphorylation and neuronal death (PMID:12514131) and is reinforced through direct association with JIP scaffolds to form the POSH-JIP apoptotic complex (PMID:16571722). This pro-apoptotic output is gated by the PI3K/Akt axis: Akt phosphorylates POSH at Ser304 within the Rac-binding domain to weaken Rac binding and apoptosis, and phosphorylates MLK3 within the complex to promote its disassembly (PMID:14504284, PMID:17535800). Complex activity is further tuned by stabilizing partners Siah1 and Nix, which amplify JNK-driven apoptosis in a POSH-dependent manner (PMID:16230351, PMID:17095503), and by the homolog Sh3rf2/POSHER, which directs POSH for proteasomal degradation via a RING-dependent mechanism (PMID:22128169). Independently of its scaffold role, POSH functions as a RING-dependent E3 ligase whose ubiquitination output regulates membrane and channel trafficking and protein stability: it controls trans-Golgi sorting required for HIV-1 Gag plasma-membrane targeting (PMID:15659549), ubiquitinates Hrs on early endosomes (PMID:16084064), drives endocytosis of ROMK1 potassium channels (PMID:19710010), catalyzes K63-linked ubiquitination of Herp to govern ER calcium homeostasis (PMID:17420289) and of ALIX (PMID:19393081), and degrades the Hippo-pathway component Expanded in Drosophila (PMID:29440430, PMID:37699871). In the nervous system POSH localizes to the leading-process cytoplasmic dilation to position activated Rac1 and assemble F-actin for neuronal migration (PMID:22959435), and at excitatory synapses it assembles the NMDAR/PSD-95/SHANK complex, with RAC1-GTP-dependent membrane recruitment enabling SRC activation in a self-limiting feedback loop; its loss produces autism-like phenotypes (PMID:35385725, PMID:42058917). In T cells POSH integrates JNK, NF-κB, and Akt signaling to control effector differentiation and survival (PMID:27084103, PMID:40672960).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1998 High

    Established POSH as a direct Rac effector, answering how Rac is physically linked to downstream JNK/NF-κB activation and apoptosis.

    Evidence Yeast two-hybrid against activated Rac plus ectopic overexpression with JNK/NF-κB and apoptosis assays in fibroblasts

    PMID:9482736

    Open questions at the time
    • Did not define the kinase intermediates between POSH and JNK
    • Overexpression-based apoptosis readout, no endogenous loss-of-function
  2. 2003 High

    Defined POSH as the physical scaffold assembling the full JNK kinase cascade, explaining how it transduces Rac signals into neuronal apoptosis.

    Evidence Reciprocal Co-IP (in vivo/in vitro), dominant-negative epistasis, antisense and siRNA in primary neurons

    PMID:12514131

    Open questions at the time
    • Did not resolve stoichiometry or order of complex assembly
    • Mechanism of complex activation by upstream stimuli unclear
  3. 2003 High

    Showed the POSH-JNK module is negatively controlled by Akt, defining a survival brake on pro-apoptotic signaling.

    Evidence Co-IP, POSH W489A mutant, PI3K/Akt inhibitors, and kinase assays showing Akt2 phosphorylation of MLK3 within the complex

    PMID:14504284

    Open questions at the time
    • Did not identify all Akt phosphosites on the complex
    • In vivo physiological relevance of disassembly not tested
  4. 2005 High

    Identified POSH's E3 ligase (RING) activity as essential for trans-Golgi protein sorting, extending its function beyond JNK scaffolding.

    Evidence siRNA knockdown with RING-mutant complementation, confocal microscopy, and HIV-1 Gag/virus release assays

    PMID:15659549

    Open questions at the time
    • Endogenous cellular substrate at the TGN not identified
    • Link between sorting role and JNK scaffolding unresolved
  5. 2005 Medium

    Revealed positive-feedback amplification of POSH-driven apoptosis through Siah1 and through Hrs ubiquitination, refining the regulatory logic of the JNK complex.

    Evidence Yeast two-hybrid, Co-IP, siRNA, mutagenesis, and ubiquitination/domain-mapping assays (Siah1; Hrs on endosomes)

    PMID:16084064 PMID:16230351

    Open questions at the time
    • Hrs ubiquitination linkage type not defined here
    • Single-lab findings without reciprocal cross-validation
  6. 2006 High

    Showed POSH directly partners with JIP scaffolds (PJAC) and with Nix/ALG-2/ALIX, defining the partner network that assembles and tunes the apoptotic JNK complex.

    Evidence Co-IP, direct binding, dominant-negative interference, yeast two-hybrid, and Drosophila genetic epistasis

    PMID:16571722 PMID:16698022 PMID:17095503

    Open questions at the time
    • Spatial coordination of POSH-JIP assembly not resolved
    • Calcium-dependence of ALG-2/ALIX interaction mechanistically undefined
  7. 2007 High

    Established POSH as a K63-linkage E3 ligase coupling its activity to ER calcium homeostasis via Herp, and pinpointed Ser304 as the Akt site that disengages Rac binding.

    Evidence In vitro K63-specific ubiquitination assays, confocal microscopy, dominant-negative/siRNA, and in vitro kinase assay with S304D/S304E phosphomimetics

    PMID:17420289 PMID:17535800

    Open questions at the time
    • How Herp both activates and is targeted by POSH not fully mechanized
    • Cellular triggers determining linkage specificity unknown
  8. 2009 High

    Extended POSH ubiquitin-ligase function to membrane channel trafficking and to non-degradative regulation, broadening its substrate repertoire.

    Evidence Co-IP, GST pulldown, in vitro ubiquitination, surface biotinylation, electrophysiology, and RING-mutant complementation (ROMK1; ALIX)

    PMID:19393081 PMID:19710010

    Open questions at the time
    • Determinants of substrate selection across diverse targets unknown
    • ALIX ubiquitination consequence beyond virus release unclear
  9. 2011 Medium

    Defined POSH protein abundance as a controlled node via Sh3rf2/POSHER-mediated degradation and Siah2 binding, linking POSH levels to apoptotic threshold and cancer cell survival.

    Evidence siRNA epistasis, proteasome inhibition, RING-mutant analysis, yeast two-hybrid domain mapping, caspase-8 assays

    PMID:21586138 PMID:22128169

    Open questions at the time
    • Whether Sh3rf2 directly ubiquitinates POSH not definitively shown
    • Scaffold vs. ligase contribution to survival not separated
  10. 2012 High

    Demonstrated POSH spatially concentrates activated Rac1 and F-actin in the leading process to drive neuronal migration in vivo, linking its Rac-effector role to cytoskeletal control.

    Evidence In utero electroporation knockdown, confocal imaging, F-actin staining, activated-Rac1 localization in migrating neurons

    PMID:22959435

    Open questions at the time
    • Molecular mechanism of F-actin assembly downstream of POSH unresolved
    • Relationship to JNK scaffolding in migration not dissected
  11. 2008 Medium

    Linked POSH to actomyosin-based outgrowth inhibition and to the Nogo66/PirB axis through Shroom3, broadening its neuronal cytoskeletal roles.

    Evidence RNAi with SH3-domain complementation, myosin II inhibition, and LZK/Shroom3 epistasis in cortical/cerebellar neurons

    PMID:18829867 PMID:20926658

    Open questions at the time
    • Direct biochemical mechanism connecting POSH to Rho-kinase/Shroom3 not defined
    • Single-lab epistasis without structural detail
  12. 2016 Medium

    Established POSH as a cell-type-specific signal integrator in T cells coordinating JNK and Tak1 signaling to control differentiation and survival.

    Evidence POSH/JIP-1 complex disruption, immunoblotting for JNK1/JNK2 and Tak1, flow cytometry, and adoptive transfer tumor models in CD8+ and CD4+ T cells

    PMID:23963642 PMID:27084103

    Open questions at the time
    • Basis of CD4 vs CD8 complex-composition differences not molecularly resolved
    • Dominant-negative disruption not equivalent to clean genetic loss
  13. 2018 High

    Defined POSH as an E3 ligase regulating Hippo signaling through degradation of Expanded, identifying a conserved developmental growth-control role.

    Evidence Drosophila genetic epistasis, Co-IP, ubiquitination assays, and tissue overgrowth/reporter assays (with E2 partner Bruce in a later study)

    PMID:29440430 PMID:37699871

    Open questions at the time
    • Conservation of Expanded regulation in mammals not shown
    • How Crumbs signals to POSH activation undefined
  14. 2022 High

    Identified POSH as a structural organizer of the postsynaptic NMDAR/PSD-95/SHANK complex required for normal synaptic transmission and behavior.

    Evidence Co-IP, POSH conditional knockout mice, electrophysiology, dendritic spine imaging, and behavioral assays

    PMID:35385725

    Open questions at the time
    • Whether scaffold or ligase activity drives synaptic clustering not separated
    • Direct binding interfaces to PSD-95/SHANK not mapped
  15. 2026 Medium

    Defined POSH as a RAC1-GTP-gated rheostat that recruits to the membrane to activate SRC at NMDAR complexes within a self-limiting feedback loop.

    Evidence POSH conditional knockout mice, Co-IP, synaptic fractionation, RAC1-GTP pulldown, SRC activity assays, and live imaging

    PMID:42058917

    Open questions at the time
    • Direct mechanism of SRC activation by POSH not biochemically resolved
    • How prolonged activation depletes POSH/SRC mechanistically unclear
  16. 2025 Medium

    Showed POSH coordinates JNK, NF-κB, and Akt simultaneously in CD8+ T cells to control effector and memory-precursor fate in vivo.

    Evidence POSH conditional knockout (CD4-Cre, GzmB-Cre) mice, flow cytometry, immunoblotting, and VSV-OVA adoptive-transfer infection

    PMID:40672960

    Open questions at the time
    • Molecular basis for simultaneous three-pathway integration undefined
    • Whether E3 activity is required in T cells not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how POSH's substrate specificity is determined across its many ubiquitination targets and how its scaffold versus E3-ligase activities are partitioned within a given cell.
  • No structural model of POSH multidomain organization or substrate engagement
  • No unifying mechanism linking spatial localization to choice of substrate or signaling output

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016874 ligase activity 6 GO:0140096 catalytic activity, acting on a protein 5 GO:0060090 molecular adaptor activity 3 GO:0008092 cytoskeletal protein binding 2
Localization
GO:0005768 endosome 2 GO:0005794 Golgi apparatus 2 GO:0005829 cytosol 2 GO:0005856 cytoskeleton 2 GO:0005886 plasma membrane 2
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-392499 Metabolism of proteins 4 R-HSA-5357801 Programmed Cell Death 4 R-HSA-112316 Neuronal System 3 R-HSA-168256 Immune System 3
Partners
AKT2JIP1MKK4MKK7MLK3PSD-95RAC1SIAH1
Complex memberships
NMDAR/PSD-95/POSH/SHANK postsynaptic complexPOSH-JIP apoptotic complex (PJAC)

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 POSH (SH3RF1) was identified as a direct target of activated Rac GTPase via yeast two-hybrid selection. POSH contains four SH3 domains and its ectopic expression activates the JNK pathway and induces nuclear translocation of NF-κB. Overexpression in fibroblasts induces apoptosis, establishing POSH as a Rac effector scaffold linking Rac to JNK/NF-κB signaling. Yeast two-hybrid selection, ectopic overexpression with JNK/NF-κB activity assays The EMBO journal High 9482736
2003 POSH acts as a scaffold for a multiprotein JNK apoptotic complex. POSH binds GTP-Rac1 and also binds mixed-lineage kinases (MLKs) both in vivo and in vitro, and complexes with MKK4, MKK7, and JNKs. POSH overexpression promotes apoptotic neuronal death suppressed by dominant-negative MLKs, MKK4/7, and c-Jun; POSH antisense oligonucleotides and siRNA suppress c-Jun phosphorylation and neuronal apoptosis induced by NGF withdrawal. Co-immunoprecipitation (in vivo and in vitro binding), dominant-negative epistasis, antisense oligonucleotides, siRNA knockdown in primary neurons The EMBO journal High 12514131
2003 Akt2 negatively regulates the POSH-MLK-JNK signaling complex. POSH binds Akt2; a POSH W489A mutant unable to bind Akt2 shows enhanced MLK3 binding and increased JNK activation. Inhibition of PI3K/Akt signaling increases MLK3 association with POSH. Akt2 phosphorylates MLK3 within the POSH complex, promoting complex disassembly and JNK pathway downregulation. Co-immunoprecipitation, mutagenesis (POSH W489A), PI3K/Akt inhibitor treatment, kinase assay The Journal of biological chemistry High 14504284
2005 Human POSH (hPOSH) is localized to the trans-Golgi network and is essential for HIV-1 Gag targeting to the plasma membrane. siRNA silencing of hPOSH ablates virus secretion and Gag plasma membrane localization. Reintroduction of native but not a RING finger mutant hPOSH restores virus release, indicating that POSH's E3 ubiquitin ligase (RING finger) activity is required for protein sorting at the trans-Golgi network. siRNA knockdown, RING finger mutant complementation, confocal microscopy, virus release assays Proceedings of the National Academy of Sciences of the United States of America High 15659549
2005 Siah1 is a binding partner of POSH and promotes apoptosis by activating the JNK pathway through POSH. Siah1's E3 ligase activity is required for its proapoptotic function. Apoptotic stimuli stabilize Siah1 protein in a JNK pathway-dependent manner requiring interaction with POSH; phosphorylation of Siah1 at tyrosines 100 and 126 enhances this stabilization, forming a positive feedback loop. Yeast two-hybrid, co-immunoprecipitation, siRNA knockdown, mutagenesis of Siah1 phosphorylation sites The Journal of biological chemistry High 16230351
2005 POSH is an E3 ubiquitin ligase for Hrs (hepatocyte growth factor-regulated tyrosine kinase substrate) on early endosomes. POSH colocalizes with Hrs on early endosomes via interaction with POSH's two C-terminal SH3 domains. The RING domain of POSH regulates Hrs stability through ubiquitin-proteasomal degradation. JNK1 binding to POSH reduces POSH-catalyzed ubiquitination of Hrs, indicating reciprocal regulation between POSH's scaffold and E3 ligase activities. Co-immunoprecipitation, confocal colocalization, ubiquitination assay, domain mapping Cellular signalling Medium 16084064
2005 POSH knockdown in rat hippocampus is neuroprotective after cerebral ischemia by reducing activation of the MLK3-MKK4-JNK pathway. Co-immunoprecipitation showed enhanced interactions of MLK3, MKK4, and phospho-JNKs with POSH during reperfusion. POSH antisense oligodeoxynucleotides reduced POSH protein, decreased these interactions, attenuated JNK pathway activation, and increased neuronal survival in CA1. Co-immunoprecipitation, antisense oligodeoxynucleotides (intracerebroventricular infusion), immunohistochemistry, western blot Journal of neurochemistry Medium 16248889
2006 POSH and JIP scaffold proteins directly associate to form a POSH-JIP apoptotic complex (PJAC) containing all kinase components of the apoptotic JNK pathway (MLKs, MKK4/7, JNKs). This POSH-JIP interaction is required for JNK activation and apoptotic cell death in response to apoptotic stimuli. Co-immunoprecipitation, direct binding assays, dominant-negative interference, epistasis The Journal of biological chemistry High 16571722
2006 Nix (a pro-apoptotic BH3-only protein) directly interacts with POSH via yeast two-hybrid and co-immunoprecipitation. Nix promotes apoptosis and JNK/c-Jun activation in a POSH-dependent manner; in cells lacking POSH, Nix does not promote JNK/c-Jun phosphorylation or apoptosis. Nix and POSH mutually stabilize each other. Yeast two-hybrid, co-immunoprecipitation, in vitro binding, loss-of-function (POSH-negative cells), overexpression with JNK/apoptosis readout The Journal of biological chemistry Medium 17095503
2006 Drosophila POSH forms a complex with ALG-2 and ALIX in a calcium-dependent manner. Overexpression of ALG-2 or ALIX induces ectopic JNK activation, and POSH co-overexpression enhances these phenotypes, suggesting POSH/ALG-2/ALIX function together in regulation of the JNK pathway. Co-immunoprecipitation, Drosophila genetic overexpression, JNK activation assay FEBS letters Medium 16698022
2007 POSH is an E3 ubiquitin ligase that regulates calcium homeostasis through spatial control of Herp. Herp is both a substrate and activator of POSH; Herp-mediated POSH activation requires the Ubl domain and promotes K63-linked polyubiquitination exclusively. Calcium perturbation (thapsigargin) induces POSH-dependent K63 ubiquitination of Herp which is required for Herp relocalization from trans-Golgi network to ER. POSH overexpression attenuates while dominant-negative POSH or siRNA enhances thapsigargin-induced calcium burst. In vitro ubiquitination assay, confocal microscopy, dominant-negative overexpression, siRNA, K63-linkage-specific ubiquitination assay The Journal of cell biology High 17420289
2007 POSH is a direct substrate for phosphorylation by Akt in vivo and in vitro. Serine 304 within the Rac-binding domain is a major Akt phosphorylation site. Phosphorylation at S304 reduces POSH binding to activated Rac, and phosphomimetic mutations S304D and S304E reduce both Rac binding and POSH-induced apoptosis. In vitro kinase assay, site-directed mutagenesis (S304D, S304E), co-immunoprecipitation, apoptosis assay The Journal of biological chemistry High 17535800
2008 POSH negatively regulates axon outgrowth via its third SH3 domain interaction with the actomyosin regulatory protein Shroom3. POSH RNAi enhances axon outgrowth; complementation requires the third SH3 domain. Shroom3 recruits Rho kinase to inhibit process outgrowth, and myosin II inhibition reverses the POSH/Shroom3 RNAi phenotype, indicating POSH-Shroom3 inhibit outgrowth through the actin-myosin network. RNAi knockdown in primary neurons, SH3 domain complementation analysis, dominant-negative approaches, myosin II inhibition Molecular biology of the cell Medium 18829867
2009 POSH acts as an E3 ubiquitin ligase for ROMK1 (Kir1.1) potassium channels, stimulating their ubiquitination and clathrin-independent, dynamin-dependent endocytosis. POSH binds ROMK1 at its N-terminus. POSH overexpression decreases surface expression and potassium currents in a RING-domain-dependent manner; POSH deltaRING mutant abolishes both ubiquitination and current inhibition. In vitro ubiquitination assays confirm POSH E3 activity toward ROMK. Co-immunoprecipitation, GST pulldown, in vitro ubiquitination assay, biotinylation surface expression assay, electrophysiology, RING domain deletion mutant The Journal of biological chemistry High 19710010
2009 POSH interacts with ALIX and functions as its E3 ubiquitin ligase in human cells, inducing K63-linked ubiquitination of ALIX on multiple lysine residues in vivo and in vitro. Wild-type POSH but not the RING finger mutant (POSHV14A) enhances ALIX-mediated HIV-1 YPXnL-dependent virus release. This ubiquitination does not destabilize ALIX, suggesting a regulatory function. Co-immunoprecipitation, in vitro ubiquitination assay, RING finger mutant, virus release assay BMC biochemistry Medium 19393081
2010 POSH is required for normal Drosophila embryogenesis and epidermal dorsal closure. In posh null mutants, F-actin accumulation and adherens junction formation are defective during dorsal closure. POSH acts downstream of dTAB2 and upstream of dTAK1 in the TNF (Eiger)-JNK signaling pathway. Drosophila null mutant analysis, genetic epistasis, F-actin staining, adherens junction imaging Journal of genetics and genomics Medium 20933214
2011 Sh3rf2 (POSHER), a homologue of POSH, promotes proteasomal degradation of POSH through a mechanism requiring the RING domains of both proteins. Sh3rf2 knockdown stabilizes POSH protein, activates JNK signaling, and causes apoptosis of neuronal cells. Apoptotic stimuli rapidly decrease Sh3rf2 levels, thereby stabilizing POSH and activating JNK-driven death. siRNA knockdown of Sh3rf2 and POSH, proteasome inhibitor assays, dominant-negative RING mutants, western blot for protein stability The Journal of biological chemistry Medium 22128169
2011 POSH and Siah2 physically interact (confirmed by yeast two-hybrid and co-immunoprecipitation); the RPxAxVxP motif in POSH's spacer region (aa 601-607) is the Siah2 binding site. Both POSH and Siah2 mediate resistance to death-receptor (TRAIL/Fas ligand)-induced caspase-8 activation in prostate cancer cells; POSH protein levels (not solely its E3 activity) are critical for maintaining viability. siRNA screen, co-immunoprecipitation, yeast two-hybrid domain mapping, caspase-8 activity assay Molecular cancer Medium 21586138
2012 POSH is concentrated in the proximal cytoplasmic dilation of the leading process (PCDLP) of migratory neocortical neurons and is essential for neuronal migration in vivo. POSH knockdown impairs PCDLP formation, centrosome translocation, and nucleokinesis. POSH colocalizes with F-actin and activated Rac1; its knockdown impairs F-actin assembly and delocalizes activated Rac1. Disruption of Rac1 activity also disrupts F-actin assembly and PCDLP formation. In utero electroporation knockdown, confocal imaging, F-actin staining, activated Rac1 localization Cell reports High 22959435
2013 POSH and JIP-1 form a multiprotein scaffold network (POSH/JIP-1) in CD8+ T cells that specifically regulates TCR-mediated JNK1 (not JNK2) activation. Disruption of the POSH/JIP-1 complex impairs JNK1 activation, reduces c-Jun, T-bet, and Eomesodermin induction, and results in defective proliferation, cytokine expression, and tumor control. Dominant-negative disruption of POSH/JIP-1 complex, immunoblotting for JNK1/2 activation, adoptive transfer tumor models European journal of immunology Medium 23963642
2015 Drosophila POSH and TAK1 regulate synaptic growth downstream of Rab8 at the neuromuscular junction. In Rab8 mutant synapses, POSH (as an endosomal JNK scaffold) and TAK1 (a JNK kinase kinase) are required for JNK/AP-1 overactivation that drives synaptic overgrowth. Recycling endosomes serve as a key compartment for POSH-mediated synaptic growth regulation. Drosophila genetic screen, mutant analysis, genetic epistasis, JNK/AP-1 signaling assays The Journal of cell biology Medium 25800055
2015 POSH is an intracellular signal transducer for the axon outgrowth inhibitor Nogo66, acting downstream of the PirB receptor. POSH RNAi in cortical and cerebellar granule neurons releases cells from myelin/Nogo66 inhibition. Leucine zipper kinase (LZK) operates downstream of NogoA/PirB in a POSH-dependent manner; Shroom3 is also a POSH-associated effector in this pathway. RNAi knockdown in cortical/cerebellar neurons, suppression analysis (LZK epistasis), process outgrowth assays with Nogo66/myelin The Journal of neuroscience Medium 20926658
2016 POSH regulates CD4+ T cell differentiation and survival through a Tak1-dependent mechanism. Disruption of POSH in CD4+ T cells leads to loss of Tak1-dependent JNK1/2 activation, decreased survival, and skewing toward Th2 differentiation. The POSH scaffold complex composition and POSH post-translational modifications differ between CD4+ and CD8+ T cells, indicating cell-type-specific mechanisms. POSH complex disruption, immunoblotting for JNK1/2 and Tak1, flow cytometry for T cell fate, apoptosis assays Journal of immunology Medium 27084103
2017 SH3RF1 (POSH) is an E3 ubiquitin ligase that acts as a negative post-translational regulator of FAT1 cadherin protein levels. Identified by yeast two-hybrid screen against FAT1 cytoplasmic tail juxtamembrane region. siRNA-mediated ablation of SH3RF1 increases cellular FAT1 protein levels and stabilizes FAT1 at the cell surface, while SH3RF1 overexpression reduces FAT1 levels. Yeast two-hybrid, siRNA knockdown, overexpression, cell surface expression assay FEBS letters Medium 28129444
2017 POSH participates in epilepsy by increasing surface expression of NMDA receptors. Co-immunoprecipitation demonstrated POSH-NMDAR1 interaction. POSH overexpression increased while knockdown decreased mEPSCs and NMDAR-mediated currents, and altered surface NMDAR1 expression in hippocampus of epileptic mice. Co-immunoprecipitation, lentiviral knockdown/overexpression, whole-cell patch-clamp electrophysiology, western blot for surface NMDAR1 Expert opinion on therapeutic targets Medium 29057721
2018 POSH is a key regulator of Hippo signaling in Drosophila through ubiquitin-mediated degradation of Expanded (Ex). POSH binds the C-terminal of Ex and is essential for Crumbs-induced ubiquitination and degradation of Ex. POSH overexpression synergizes with loss of Kibra to induce tissue overgrowth and upregulation of Hippo target genes; POSH knockdown impedes Yorkie-dependent intestinal stem cell renewal. Genetic epistasis in Drosophila, co-immunoprecipitation, ubiquitination assay, tissue overgrowth/reporter assays Proceedings of the National Academy of Sciences of the United States of America High 29440430
2018 POSH/SH3RF1 mediates neuropathology in Drosophila and mammalian models of CHMP2BIntron5-associated frontotemporal dementia. CHMP2BIntron5 expression causes aberrant, AKT-dependent accumulation of POSH throughout the nervous system. POSH knockdown is neuroprotective, alleviating neuronal morphology defects, behavioral deficits, premature lethality, dendritic collapse, and reducing elevated JNK/apoptotic markers. Drosophila and rat primary neuron models, POSH knockdown, AKT inhibition, JNK/apoptotic marker quantification, behavioral assays Human molecular genetics Medium 29432529
2022 POSH directly interacts with PSD-95 and SHANK2/3 at excitatory synapses, assembling the NMDAR/PSD-95/POSH/SHANK complex. In POSH conditional knockout mice, synaptic clustering of the NMDAR/PSD-95/SHANK complex is disrupted, accompanied by abnormal dendritic spine development, impaired glutamatergic transmission, and autism-like behaviors (social deficits, repetitive behaviors, learning/memory impairment). Co-immunoprecipitation, POSH conditional knockout mice, electrophysiology (glutamatergic transmission), dendritic spine imaging, behavioral assays Cell reports High 35385725
2023 SH3RF1 mediates K63-linked ubiquitination of snakehead vesiculovirus phosphoprotein (P) specifically at lysine 264, facilitating viral replication and maintaining P protein stability. Identified through RNAi screening of cellular E3 ligases; SH3RF1 interacted with and ubiquitinated SHVV-P, and K264R mutation abolished K264 ubiquitination and reduced SHVV replication. 4D label-free ubiquitome analysis, RNAi screening, co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis (K264R), virus replication assay International journal of biological macromolecules Medium 37979762
2023 Bruce (E2 ubiquitin-conjugating enzyme) synergizes with POSH (E3 ligase) to regulate ubiquitination-mediated degradation of Expanded (Ex) in Drosophila Hippo signaling. Bruce acts upstream of Ex but in parallel with canonical Hippo-Warts cascade. Loss of Bruce suppresses POSH-mediated wing overgrowth and Hippo target gene expression. Drosophila genetic screen, genetic epistasis, ubiquitination assay, tissue overgrowth quantification Cell death & disease Medium 37699871
2026 POSH loss reduces SRC postsynaptic enrichment and weakens SRC-NMDAR-PSD-95 complex interactions. NMDAR activation triggers RAC1-GTP-dependent recruitment of POSH to the membrane, leading to NMDAR-induced SRC activation. Prolonged NMDAR activation depletes both POSH and SRC, establishing a negative feedback loop that prevents NMDAR hyperexcitation. POSH acts as a molecular rheostat integrating RAC1-driven membrane targeting with SRC activation. POSH conditional knockout mice, co-immunoprecipitation, synaptic fractionation, RAC1-GTP pulldown, SRC activity assays, live imaging iScience Medium 42058917
2025 POSH is essential for coordinating JNK, NF-κB, and Akt signaling in CD8+ T cells. POSH conditional knockout (POSHfl/fl CD4-Cre and GzmB-Cre) mice show impaired induction of all three pathways, resulting in reduced differentiation into short-lived effector cells, delayed proliferation, and decreased survival of memory precursor cells during contraction phase. Conditional T cell POSH knockout reporter mouse models, flow cytometry, immunoblotting, adoptive transfer with VSV-OVA infection Frontiers in immunology Medium 40672960

Source papers

Stage 0 corpus · 48 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2018 Germline BRCA mutation and outcome in young-onset breast cancer (POSH): a prospective cohort study. The Lancet. Oncology 346 29337092
1998 A new rac target POSH is an SH3-containing scaffold protein involved in the JNK and NF-kappaB signalling pathways. The EMBO journal 183 9482736
2013 Prospective observational study of breast cancer treatment outcomes for UK women aged 18-40 years at diagnosis: the POSH study. Journal of the National Cancer Institute 165 23723422
2003 POSH acts as a scaffold for a multiprotein complex that mediates JNK activation in apoptosis. The EMBO journal 163 12514131
2017 Local Recurrence and Breast Oncological Surgery in Young Women With Breast Cancer: The POSH Observational Cohort Study. Annals of surgery 86 27455160
2005 The trans-Golgi network-associated human ubiquitin-protein ligase POSH is essential for HIV type 1 production. Proceedings of the National Academy of Sciences of the United States of America 69 15659549
2015 Rab8, POSH, and TAK1 regulate synaptic growth in a Drosophila model of frontotemporal dementia. The Journal of cell biology 68 25800055
2003 Akt2 negatively regulates assembly of the POSH-MLK-JNK signaling complex. The Journal of biological chemistry 62 14504284
2012 POSH localizes activated Rac1 to control the formation of cytoplasmic dilation of the leading process and neuronal migration. Cell reports 61 22959435
2013 Ethnicity and outcome of young breast cancer patients in the United Kingdom: the POSH study. British journal of cancer 57 24149174
2006 Direct interaction of the molecular scaffolds POSH and JIP is required for apoptotic activation of JNKs. The Journal of biological chemistry 57 16571722
2005 Siah1 interacts with the scaffold protein POSH to promote JNK activation and apoptosis. The Journal of biological chemistry 56 16230351
2007 Prospective study of Outcomes in Sporadic versus Hereditary breast cancer (POSH): study protocol. BMC cancer 45 17697367
2007 The ubiquitin E3 ligase POSH regulates calcium homeostasis through spatial control of Herp. The Journal of cell biology 40 17420289
2010 POSH is an intracellular signal transducer for the axon outgrowth inhibitor Nogo66. The Journal of neuroscience : the official journal of the Society for Neuroscience 39 20926658
2005 Knock-down of POSH expression is neuroprotective through down-regulating activation of the MLK3-MKK4-JNK pathway following cerebral ischaemia in the rat hippocampal CA1 subfield. Journal of neurochemistry 39 16248889
2006 POSH, a scaffold protein for JNK signaling, binds to ALG-2 and ALIX in Drosophila. FEBS letters 38 16698022
2006 Proapoptotic Nix activates the JNK pathway by interacting with POSH and mediates death in a Parkinson disease model. The Journal of biological chemistry 32 17095503
2011 Sh3rf2/POSHER protein promotes cell survival by ring-mediated proteasomal degradation of the c-Jun N-terminal kinase scaffold POSH (Plenty of SH3s) protein. The Journal of biological chemistry 31 22128169
2008 The scaffold protein POSH regulates axon outgrowth. Molecular biology of the cell 30 18829867
2005 Novel function of POSH, a JNK scaffold, as an E3 ubiquitin ligase for the Hrs stability on early endosomes. Cellular signalling 30 16084064
2011 Possible role of death receptor-mediated apoptosis by the E3 ubiquitin ligases Siah2 and POSH. Molecular cancer 27 21586138
2018 POSH regulates Hippo signaling through ubiquitin-mediated expanded degradation. Proceedings of the National Academy of Sciences of the United States of America 25 29440430
2015 Family history and outcome of young patients with breast cancer in the UK (POSH study). The British journal of surgery 25 25989914
2009 POSH stimulates the ubiquitination and the clathrin-independent endocytosis of ROMK1 channels. The Journal of biological chemistry 25 19710010
2022 POSH regulates assembly of the NMDAR/PSD-95/Shank complex and synaptic function. Cell reports 23 35385725
2007 Regulation of the Pro-apoptotic scaffolding protein POSH by Akt. The Journal of biological chemistry 22 17535800
2009 Exploring the functional interaction between POSH and ALIX and the relevance to HIV-1 release. BMC biochemistry 21 19393081
2005 The assembly of POSH-JNK regulates Xenopus anterior neural development. Developmental biology 15 16125690
2018 Increased circulating resistin levels in early-onset breast cancer patients of normal body mass index correlate with lymph node negative involvement and longer disease free survival: a multi-center POSH cohort serum proteomics study. Breast cancer research : BCR 14 29566726
2013 The POSH/JIP-1 scaffold network regulates TCR-mediated JNK1 signals and effector function in CD8(+) T cells. European journal of immunology 14 23963642
2018 The pro-apoptotic JNK scaffold POSH/SH3RF1 mediates CHMP2BIntron5-associated toxicity in animal models of frontotemporal dementia. Human molecular genetics 13 29432529
2010 POSH promotes cell survival in Drosophila and in human RASF cells. FEBS letters 11 20974134
2006 Activation of the apoptotic JNK pathway through the Rac1-binding scaffold protein POSH. Methods in enzymology 11 16472680
2018 Molecular characterization of the apoptosis-related SH3RF1 and SH3RF2 genes and their association with exercise performance in Arabian horses. BMC veterinary research 10 30107803
2010 POSH misexpression induces caspase-dependent cell death in Drosophila. Developmental dynamics : an official publication of the American Association of Anatomists 10 20014406
2010 POSH is involved in Eiger-Basket (TNF-JNK) signaling and embryogenesis in Drosophila. Journal of genetics and genomics = Yi chuan xue bao 9 20933214
2016 POSH Regulates CD4+ T Cell Differentiation and Survival. Journal of immunology (Baltimore, Md. : 1950) 8 27084103
2013 Imputation-based association analyses identify new lung cancer susceptibility variants in CDK6 and SH3RF1 and their interactions with smoking in Chinese populations. Carcinogenesis 8 23644744
2017 Protein interaction screening identifies SH3RF1 as a new regulator of FAT1 protein levels. FEBS letters 7 28129444
2017 POSH participates in epileptogenesis by increasing the surface expression of the NMDA receptor: a promising therapeutic target for epilepsy. Expert opinion on therapeutic targets 7 29057721
2007 Identification of POSH2, a novel homologue of the c-Jun N-terminal kinase scaffold protein POSH. Developmental neuroscience 7 17762203
2023 Snakehead vesiculovirus hijacks SH3RF1 for replication via mediating K63-linked ubiquitination at K264 of the phosphoprotein. International journal of biological macromolecules 4 37979762
2010 Regulation of the protein stability of POSH and MLK family. Protein & cell 4 21203929
2020 Assessing the role of SH3RF1 and SH3RF2 polymorphisms in susceptibility to tuberculosis: A case-control study in the Han Chinese population. Microbial pathogenesis 2 33129950
2023 E2 enzyme Bruce negatively regulates Hippo signaling through POSH-mediated expanded degradation. Cell death & disease 1 37699871
2026 Autism-linked protein POSH balances NMDAR signaling via a self-limiting kinase-scaffold loop. iScience 0 42058917
2025 The POSH scaffold protein is essential for signal coordination leading to CD8 T cell differentiation and survival. Frontiers in immunology 0 40672960

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