Affinage

SHC1

SHC-transforming protein 1 · UniProt P29353

Length
583 aa
Mass
62.8 kDa
Annotated
2026-06-10
100 papers in source corpus 53 papers cited in narrative 53 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SHC1 (ShcA) is a modular phosphotyrosine adaptor that couples activated receptors—receptor tyrosine kinases, cytokine receptors, integrins, G-protein-coupled receptors, and mechanosensors—to downstream Ras/MAPK and PI3K/Akt signaling (PMID:8195171, PMID:10809671, PMID:10982827). It docks on activated receptors through two phosphotyrosine-reading modules: an SH2 domain that binds autophosphorylated receptors such as the PDGF beta-receptor and the EGF receptor (PMID:8195171, PMID:7925272), and a PTB domain that engages high-affinity sites such as Ret/ptc2 Tyr586 (PMID:9047384). Receptor-induced phosphorylation of ShcA at Tyr239/240 and Tyr313 creates pYXN motifs that recruit Grb2-Sos, amplifying Ras activation (PMID:7731718, PMID:10482988, PMID:10982827), and site-specific knock-in studies show these tyrosines partition distinct outputs, with Y313 driving tumor cell survival and Y239/240 driving vascularization and STAT3 immunosuppressive signaling (PMID:18273058, PMID:28276425). ShcA also reads cytokine receptors indirectly by binding JAK2 directly through its SH2 domain (growth hormone, IL-6, erythropoietin receptors), feeding the same Grb2/Ras axis (PMID:7535773, PMID:9126968, PMID:7538110), and routes PI3K/Akt activation via a Shc→Grb2→Gab2→PI3K cascade and a 14-3-3:Shc scaffold (PMID:10982827, PMID:19218246). Beyond canonical pY signaling, the PTB domain mediates non-canonical, phosphotyrosine-independent interactions with IQGAP1 to drive lamellipodia and membrane ruffling (PMID:20075861), and ShcA acts as a temporal scaffold whose Akt-mediated Ser29 feedback phosphorylation recruits the phosphatase Ptpn12 (and PTP-PEST) to switch outputs from Grb2-based mitogenic signaling toward cytoskeletal/trafficking pathways (PMID:12052829, PMID:23846654). ShcA controls receptor compartmentalization, sequestering TGF-beta receptors to caveolin compartments to suppress Smad-driven EMT while enabling Erk signaling (PMID:17673906, PMID:26680585). Through its p66 isoform, ShcA reports cell attachment at focal adhesions to restrain Ras and enforce anoikis, and generates ROS via NADPH oxidase under mechanical stretch to regulate vascular stress responses (PMID:20676142, PMID:24842918). Genetically, ShcA is required in vivo for cardiovascular development, pre-TCR and TCR signaling in T cells, neuronal survival, and mammary tumorigenesis, with the p52 isoform identified as the oncogenic driver of breast cancer initiation (PMID:10809671, PMID:12101399, PMID:11917142, PMID:10985347, PMID:31202267).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1994 High

    Established that ShcA is a direct phosphotyrosine adaptor for activated receptor tyrosine kinases, defining how it physically engages receptors and links them to Grb2/Ras.

    Evidence GST-SH2 pulldown with purified PDGF beta-receptor plus mutagenesis, and in vivo EGFR co-IP with subcellular fractionation

    PMID:7925272 PMID:8195171

    Open questions at the time
    • Whether receptor-specific compartmentalization (endosomal vs. plasma membrane) is general across all RTKs was not resolved
    • The functional consequence of isoform-preferential phosphorylation was not yet established
  2. 1995 High

    Defined the pYXN/Grb2-recruitment logic and showed ShcA integrates non-RTK inputs (GPCR Gβγ, JAK2 from cytokine receptors), establishing it as a convergence node for diverse upstream signals.

    Evidence BIAcore binding of Tyr317-phosphorylated Shc to Grb2 with functional migration readout; co-IP and pharmacological dissection of Gβγ- and JAK2-driven Shc phosphorylation

    PMID:7535773 PMID:7544794 PMID:7568118 PMID:7731718

    Open questions at the time
    • Whether SH2 vs. PTB docking dominates was receptor-dependent and not unified
    • In vivo relevance of GPCR-to-Shc coupling not tested genetically
  3. 1996 High

    Showed ShcA couples integrins, not just soluble growth factors, to MAPK and cell-cycle progression, and identified phosphotyrosine-independent interactions (adaptins) that hint at trafficking roles.

    Evidence Dominant-negative Shc, integrin alpha-subunit domain swaps and co-IP; GST-Shc affinity chromatography mapping adaptin binding to the CH1 region

    PMID:8617812 PMID:8929541

    Open questions at the time
    • The mechanism linking caveolin to integrin-Shc recruitment was not molecularly resolved
    • Functional consequence of Shc-adaptin binding for endocytosis untested
  4. 1997 High

    Distinguished the high-affinity PTB-domain docking mode from SH2 docking and extended Shc engagement to cytokine receptors and adhesion molecules, clarifying domain-specific receptor selection.

    Evidence In vitro PTB vs. SH2 binding to Ret/ptc2 with Y586F mutagenesis; gp130/Jak2 domain-specific co-IP; cadherin SH2 binding by yeast two-hybrid and in vitro pulldown

    PMID:9047384 PMID:9126968 PMID:9153187

    Open questions at the time
    • Whether PTB and SH2 occupancy is simultaneous or competitive on a given receptor not addressed
    • Physiological output of cadherin-Shc binding not defined
  5. 1998 High

    Provided in vivo genetic proof that Shc recruitment is required for tumor progression and that PTB-mediated docking can require accessory localization factors.

    Evidence Transgenic PyV MT Shc-binding-site mutants with biochemical reversion analysis; chimeric Ret/ptc2 receptors with Enigma co-localization and Ras/Raf epistasis

    PMID:9528800 PMID:9528804

    Open questions at the time
    • Which downstream Shc effector (Ras vs. PI3K) drives metastasis was not isolated here
    • Generality of localization-dependent PTB signaling beyond Ret unknown
  6. 1999 Medium

    Resolved that ShcA bidirectionally regulates migration vs. proliferation through distinct domains and is counter-regulated by phosphatases, establishing it as a tunable signaling switch.

    Evidence Domain-specific Shc mutants in migration/proliferation assays; in vitro PTEN phosphatase assay on Shc and SHIP co-IP via PTB domain

    PMID:10427092 PMID:10482988 PMID:10613912

    Open questions at the time
    • The PAL SH2 interaction rests on a single yeast two-hybrid result without in-cell validation (#18)
    • Direct phosphatase competition with kinase input not quantified in vivo
  7. 2000 High

    Genetic knockout and pathway reconstitution established ShcA's essential developmental role and ordered the Shc→Grb2→Gab2→PI3K/Akt cascade alongside parallel ERK pathways.

    Evidence ShcA-null mice with cardiovascular defects and MAPK analysis; chimeric cytokine-receptor reconstitution defining Gab2/PI3K pathway order; parallel Shc vs. FAK ERK dissection

    PMID:10809671 PMID:10976102 PMID:10982827 PMID:10985347 PMID:7538110

    Open questions at the time
    • How Shc selects between Ras/MAPK and PI3K/Akt outputs was not mechanistically resolved
    • Tissue-specific domain requirements not yet dissected
  8. 2002 High

    Established isoform-specific c-Src activation and PTM-dependent phosphatase recruitment, and demonstrated ShcA's requirement in T-cell development and TCR signaling order.

    Evidence In vitro c-Src activation assay with Shc point mutants; Ser29/Ser138 phosphosite mapping with S29A mutants and PTP-PEST co-IP; conditional Shc KO and dominant-negative thymocytes; Shc-deficient Jurkat complementation defining Shc→MAPK→c-Rel→IL-2

    PMID:11773443 PMID:11884411 PMID:11917142 PMID:12048194 PMID:12052829 PMID:12101399

    Open questions at the time
    • The full set of serine kinases controlling PTP-PEST recruitment in distinct receptor contexts not enumerated
    • Isoform-specific c-Src activation mechanism structurally undefined
  9. 2007 High

    Revealed that ShcA carries non-canonical signaling, being directly phosphorylated by the TGF-beta receptor (a dual-specificity kinase) and using combinatorial domain requirements for distinct developmental programs.

    Evidence In vitro TbetaRI kinase assays with kinase-dead mutants and Erk readouts; domain-specific knock-in mice (PTB-dead, pYXN mutants) for heart and muscle spindle phenotypes

    PMID:17626887 PMID:17673906

    Open questions at the time
    • How a single receptor selects ShcA-Erk vs. Smad outputs was not yet defined
    • Structural basis for combinatorial PTB/SH2/pYXN cooperation not determined
  10. 2008 High

    Site-specific knock-in genetics partitioned ShcA tyrosine outputs into discrete biological functions (survival vs. vascularization), explaining how one adaptor produces divergent tumor phenotypes.

    Evidence Endogenous-promoter pY-deficient ShcA knock-in mice with mammary tumor progression analysis

    PMID:18273058

    Open questions at the time
    • The distinct effector complexes assembled at Y313 vs. Y239/240 were not biochemically separated here
    • Quantitative contribution of each site to overall tumor burden not isolated
  11. 2010 High

    Defined ShcA's non-canonical PTB-IQGAP1 cytoskeletal axis structurally and established p66Shc as a focal-adhesion attachment reporter controlling anoikis and metastasis.

    Evidence NMR characterization of PTB-IQGAP1 binding with siRNA lamellipodia assays; p66Shc re-expression in null metastatic cells with Ras activity and in vivo metastasis assays

    PMID:20075861 PMID:20624904 PMID:20676142

    Open questions at the time
    • How PTB switches between IQGAP1, PTP-PEST and receptor ligands in cells not temporally resolved
    • Molecular basis of p66Shc Ras suppression at focal adhesions not fully defined
  12. 2013 High

    Quantitative temporal proteomics established ShcA as a dynamic scaffold whose Akt-driven Ser29 feedback phosphorylation recruits Ptpn12 to switch outputs from Grb2-mitogenic to cytoskeletal/trafficking signaling.

    Evidence Time-resolved quantitative mass spectrometry of Shc1 complexes after EGF, phosphomutant analysis, Ptpn12 co-IP and invasion assays

    PMID:23846654

    Open questions at the time
    • The full SgK269-mediated effector branch downstream of the switch is not detailed
    • Whether the same temporal switch operates at non-EGFR receptors untested
  13. 2015 High

    Showed ShcA controls signaling outcome by physically directing receptor compartmentalization, sequestering TGF-beta receptors to caveolin compartments to suppress Smad-driven EMT.

    Evidence Receptor competition co-IP, caveolin vs. clathrin fractionation, ShcA siRNA with EMT, invasion and mammosphere assays

    PMID:26680585

    Open questions at the time
    • The structural determinant routing receptors to caveolin vs. clathrin not mapped
    • Whether this compartmentalization mechanism generalizes to other receptor families unknown
  14. 2017 High

    Extended ShcA function to immune evasion and adhesion-receptor scaffolding, and to slit-diaphragm regulation, broadening its roles beyond mitogenic signaling.

    Evidence pY-deficient knock-in mice linking Y239/240 to STAT3/STAT1 balance and checkpoint sensitivity; DDR1b Y513 PTB-domain coupling to Pyk2; nephrin SH2 binding with in vivo surface-expression assays

    PMID:27605668 PMID:28276425 PMID:29018139

    Open questions at the time
    • Mechanism by which Y239/240-Shc selectively activates STAT3 not biochemically resolved
    • Direct kinase-substrate relationships in the nephrin endocytosis pathway not fully defined
  15. 2021 High

    Established ShcA as a mechanotransduction node in the endothelium, acting downstream of receptors and mechanosensors to drive vascular pathology, and identified isoform- and drug-level specificity.

    Evidence Endothelial-specific Shc genetic targeting and Alk5 reconstitution in atherosclerosis models; flow- and stretch-induced Shc/p66Shc pathway dissection; isoform-specific p52/p66 KO rats; idebenone-Shc direct binding with genetic target validation

    PMID:11369938 PMID:14665640 PMID:18606845 PMID:21454706 PMID:24842918 PMID:29500169 PMID:30290222 PMID:31202267 PMID:34244146

    Open questions at the time
    • How distinct mechanosensors converge on a common Shc activation step is not unified
    • Structural basis for p52 vs. p66 functional divergence remains undefined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ShcA integrates its many domain-specific, isoform-specific, and PTM-gated interactions into a single decision-making logic that selects among Ras/MAPK, PI3K/Akt, cytoskeletal, redox, and compartmentalization outputs in a given cell remains unresolved.
  • No unified structural/quantitative model predicting output selection from input identity
  • The full p66Shc mitochondrial redox mechanism is not represented mechanistically in this corpus
  • Interplay between competing PTB ligands (IQGAP1, PTP-PEST, receptors) in vivo not quantified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 6
Localization
GO:0005829 cytosol 2 GO:0005886 plasma membrane 2 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-1643685 Disease 4 R-HSA-1266738 Developmental Biology 3 R-HSA-168256 Immune System 3 R-HSA-1640170 Cell Cycle 2
Partners
GAB2GRB2IQGAP1JAK2PTPN12PTPN12/PTP-PESTSRCYWHAZ
Complex memberships
Shc-Grb2-Sos complexapoER2/Dab2/SHC1/PP2A complex

Evidence

Reading pass · 53 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 SHC1 (Shc) directly interacts with the autophosphorylated PDGF beta-receptor via its SH2 domain. Multiple autophosphorylation sites on the PDGF beta-receptor (Tyr-579, Tyr-740, Tyr-751, Tyr-771) mediate Shc SH2 domain binding. Receptor activation induces preferential phosphorylation of p52Shc, which then associates with Grb2. Co-immunoprecipitation, GST-SH2 domain pulldown with purified baculovirus-expressed receptor, synthetic peptide analysis, mutagenesis The Journal of biological chemistry High 8195171
1994 Following EGF stimulation in rat liver, SHC is recruited to and tyrosine-phosphorylated by the EGF receptor (primarily at pTyr-1173), associates with GRB2 and mSOS largely in endosomes, forming a cytosolic complex that links to Ras activation (evidenced by Raf-1 mobility shift). Insulin receptor activation does not detectably phosphorylate SHC or recruit GRB2/mSOS in the same cells, demonstrating receptor-specific compartmentalization. In vivo receptor stimulation, subcellular fractionation, co-immunoprecipitation, Western blotting The EMBO journal High 7925272
1994 Shc associates with the PEST tyrosine phosphatase (PTP-PEST) via its amino-terminal half (p52 and p66 but not p46 isoforms). Complex formation is stimulated 6–8-fold by PKC activator PMA but not by EGF or serum, linking G-protein receptor/PKC crosstalk to Shc regulation. Yeast two-hybrid screen, GST pulldown, co-immunoprecipitation from HeLa and neuroblastoma cells, isoform-specific analysis The Journal of biological chemistry Medium 7929214
1995 HGF receptor tyrosine phosphorylates ShcA via docking at pY1349 and pY1356 (Kd ~150 nM each via BIAcore); this leads to Shc phosphorylation at Y317, creating a high-affinity Grb2 binding site (Kd 15 nM), thereby amplifying Ras pathway activation. Overexpression of wild-type Shc but not Y317F mutant enhances HGF-induced cell migration and growth. Site-directed mutagenesis of HGF receptor, BIAcore biosensor binding assay, overexpression of wild-type vs. Y317F mutant Shc Oncogene High 7731718
1995 Gbeta-gamma subunits of heterotrimeric G proteins stimulate tyrosine phosphorylation of the Shc p46/p52 isoforms, representing an early step in Gi-coupled receptor-mediated Ras/MAP kinase activation. Phosphorylation is blocked by a G-beta-gamma-binding PH domain peptide, tyrosine kinase inhibitors, and wortmannin (PI3K inhibitor), but not by dominant-negative Ras. Overexpression of G-beta-gamma or alpha2-adrenergic receptor in COS-7 cells, anti-phosphotyrosine immunoprecipitation, anti-Shc immunoprecipitation, pertussis toxin treatment, inhibitor studies Proceedings of the National Academy of Sciences of the United States of America Medium 7568118
1995 G protein-coupled chemoattractant (N-formyl peptide) receptor activates the Src-family kinase Lyn, which binds to Shc (via the Shc SH2 domain) and phosphorylates it on tyrosine. Phospho-Shc/phospho-Lyn complexes then associate with PI3K, correlating with PI3,4,5-P3 generation. Co-immunoprecipitation from human neutrophils, Western blot, SH2-domain binding studies The Journal of biological chemistry Medium 7650013
1995 Growth hormone (GH) promotes rapid tyrosyl phosphorylation of all three ShcA isoforms (p66, p52, p46) through JAK2. The ShcA SH2 domain binds tyrosyl-phosphorylated JAK2 directly (shown with constitutively phosphorylated JAK2 in COS-7 cells). Grb2 subsequently associates with phosphorylated ShcA in a GH-dependent manner. GHR domains required for ShcA phosphorylation were mapped by mutagenesis. GST-SHC SH2 domain pulldown, co-immunoprecipitation, GHR mutagenesis in CHO cells, Western blotting The Journal of biological chemistry High 7535773
1995 MAP kinase phosphorylates the C-terminal tail of mSos1 in vitro at sites shared with EGF-stimulated cells, and this phosphorylation disrupts mSos1-Grb2 binding to Shc and the EGF receptor, providing a negative-feedback mechanism attenuating Ras activation downstream of Shc. In vitro MAP kinase phosphorylation of mSos1, tryptic phosphopeptide mapping, binding assays with phosphorylated vs. unphosphorylated mSos1 Oncogene High 7478566
1995 Insulin receptor preferentially phosphorylates the p52 ShcA isoform (4-fold higher Vmax than p46 in vitro) and shows differential binding to p52 vs. p46 in vitro; EGF receptor phosphorylates both isoforms equivalently. Grb2 predominantly associates with p52ShcA after insulin stimulation. In vitro kinase assay with purified isoforms, co-immunoprecipitation, CHO cell overexpression The Journal of biological chemistry High 7544794
1996 Shc couples a class of integrins to cell cycle progression and MAP kinase activation. The recruitment of Shc by integrins is specified by the extracellular/transmembrane domain of specific integrin alpha subunits and is mediated by caveolin. Dominant-negative Shc and mutagenesis demonstrate Shc is necessary and sufficient for integrin-mediated MAP kinase activation and cooperation with mitogens to drive G1 transit. Co-immunoprecipitation, mutagenesis, dominant-negative inhibition, integrin alpha-subunit domain swaps Cell High 8929541
1996 Shc interacts with alpha- and beta-adaptins (components of clathrin adaptor complexes involved in receptor endocytosis) via amino acids 346–355 in the collagen homologous (CH1) region. This interaction is phosphotyrosine-independent. GST-Shc affinity chromatography from bovine brain lysates, peptide sequencing, co-immunoprecipitation, domain-deletion GST-Shc mutants The Journal of biological chemistry Medium 8617812
1997 Shc mediates IL-6 signaling by associating in vivo and in vitro with phosphorylated gp130 through the Shc SH2 domain and with activated Jak2 via the Shc PTB (phosphotyrosine-binding) domain. IL-6 stimulation induces Shc-Grb2 association, linking Jak2 to the Ras/MAP kinase pathway. Co-immunoprecipitation in vivo and in vitro, domain-specific binding assays Journal of immunology Medium 9126968
1997 The Shc PTB domain binds Ret/ptc2 at Tyr586 (Tyr1062 of proto-Ret) with ~20-fold higher affinity than the Shc SH2 domain; a Y586F Ret/ptc2 mutant abolishes Shc docking. Both Shc PTB and SH2 domains interact with Ret/ptc2 in vitro. In vitro pulldown with Shc PTB and SH2 domains, site-directed mutagenesis (Y586F), co-immunoprecipitation Oncogene High 9047384
1997 ShcA interacts via its SH2 domain with the cytoplasmic domain of cadherin in a phosphotyrosine-dependent manner, demonstrated by yeast two-hybrid, co-precipitation from mammalian cells, and direct biochemical pulldown. EGF stimulation abrogates this association. Yeast two-hybrid, co-precipitation from A-431 cells, direct in vitro biochemical pulldown The Journal of biological chemistry High 9153187
1998 PyV middle T antigen-mediated mammary tumorigenesis requires both Shc and PI3K signaling: Shc-binding-site mutant MT failed to efficiently form metastatic mammary tumors in transgenic mice; metastatic tumors arising in these mice showed reversion of the Shc binding site, genetically confirming Shc's requirement for tumor progression. Transgenic mouse models with PyV MT mutants decoupled from Shc or PI3K, genetic and biochemical reversion analysis Molecular and cellular biology High 9528804
1998 The Shc PTB domain interacts with Ret/ptc2 at Tyr586 and results in Shc tyrosine phosphorylation. Mitogenic signaling from Ret/ptc2 requires both Shc recruitment (via Y586) and subcellular localization via Enigma; Shc and Enigma bind the same Ret/ptc2 site on individual monomers, so dimerization enables assembly of both. Co-immunoprecipitation, chimeric receptor constructs, dominant-negative Ras/Raf epistasis Molecular and cellular biology Medium 9528800
1999 Shc mediates random (non-directional) cell motility downstream of integrins via the MAP kinase pathway. PTEN directly dephosphorylates Shc, downregulating Shc-driven MAP kinase activation and migration. This Shc/MEK1 pathway is additive to a separate FAK/p130Cas pathway regulating directional migration. Overexpression of dominant-negative Shc, constitutively active MEK1, PTEN reconstitution, in vitro PTEN phosphatase assay on Shc, cell migration assays The Journal of cell biology High 10427092
1999 ShcA associates with SHIP (SH2-containing inositol phosphatase) via the ShcA PTB domain following FLT3 activation. ShcA is phosphorylated at Tyr239/240 and Tyr313 by FLT3; Shc overexpression increases SHIP tyrosine phosphorylation (requiring functional PTB domain) and limits FLT3-dependent cell growth (requiring Tyr313). Co-immunoprecipitation, site-directed mutagenesis (Y→F substitutions), overexpression studies, cell growth assays Leukemia Medium 10482988
1999 The Shc SH2 domain binds the phosphorylated novel protein PAL (Protein expressed in Activated Lymphocytes) in a phosphotyrosine-independent manner, identifying a non-canonical interaction mode for the Shc SH2 domain. PAL expression is restricted to proliferating cells and is growth-factor inducible. Yeast two-hybrid, domain mapping with Shc mutants Oncogene Low 10086341
1999 Shc differentially regulates cell migration vs. proliferation depending on growth factor availability: under growth-factor-limiting conditions the PTB domain drives haptotactic migration, whereas when growth factors are present the SH2 domain is selectively required for DNA synthesis. Mutational analysis of Shc PTB and SH2 domains, migration and proliferation assays under varied growth factor conditions The Journal of cell biology Medium 10613912
2000 ShcA sensitizes cells to growth factor-induced MAP kinase activation and organizes cytoskeletal rearrangement in response to extracellular matrix. ShcA-null mouse embryos exhibit cardiovascular defects (heart development and blood vessel remodeling defects), with MAP kinase pathway selectively impaired. The PTB and SH2 domains of ShcA mediate these functions. Targeted mutation/knockout of ShcA in mice, biochemical analysis of mutant cells, MAPK activation assays Genes & development High 10809671
2000 Shc activates the PI3K/Akt pathway via a Shc→Grb2→Gab2→PI3K cascade downstream of cytokine receptors (IL-3 betac, IL-2Rbeta) that lack direct p85-binding sites. Y577 (Shc binding site on betac) is the major site required for Gab2 phosphorylation. Fusion of Shc directly to mutant IL-2Rbeta demonstrates Shc is sufficient to evoke Gab2 phosphorylation; mutation of the three Shc pYXN/Grb2-binding tyrosines abolishes this. Y→F mutant and 'add-back' receptor mutants, chimeric receptors, Grb2 SH2/SH3 dominant-negative mutants, Gab2 PI3K-binding mutants, Akt activation assays Molecular and cellular biology High 10982827
2000 Shc and FAK activate ERK independently and in parallel downstream of integrins. Cytochalasin D abolishes FAK but not Shc signaling to ERK. Targeted deletion of the beta1 cytoplasmic domain segment required for FAK activation does not impair Shc tyrosine phosphorylation or ERK activation. Dominant-negative studies show Shc mediates the early/peak phase and FAK/p130CAS/Crk/Rap1 mediate the late phase of ERK activation. Cytochalasin D treatment, targeted beta1 integrin cytoplasmic domain deletion in primary fibroblasts, dominant-negative constructs, ERK activation assays The Journal of biological chemistry High 10976102
2000 EPO-induced Shc phosphorylation occurs via direct Shc SH2 domain association with JAK2 rather than requiring receptor cytoplasmic phosphotyrosines; a mitogenically deficient EPOR lacking all cytoplasmic tyrosines still supports Shc-JAK2 association and Shc phosphorylation in vitro. Co-immunoprecipitation of Shc and JAK2, in vitro cytokine-induced Shc phosphorylation assay, receptor mutants lacking tyrosines The Journal of biological chemistry Medium 7538110
2000 TrkB-mediated neuronal survival and axon growth are both dependent on the Shc binding site of TrkB, operating through PI3K and MEK pathways. TrkB mutated at the Shc site poorly supports survival and growth relative to wild-type TrkB; TrkB mutated at the PLC-gamma1 site supports both. TrkB site-directed mutants expressed in primary sympathetic neurons, PI3K and MEK inhibitor studies, survival and axon growth readouts Neuron High 10985347
2000 In EGF-stimulated A431 cells, all three ShcA isoforms (P46, P52, P66) translocate from cytoplasm to plasma membrane within 5 min and then redistribute to cytoplasmic vesicle structures co-localizing with EGF receptor and activated c-Src. P52 and P66 (but not P46) augment EGFR-Src complex formation and c-Src activation. GFP-Shc live imaging, indirect immunofluorescence, co-immunoprecipitation, synthetic peptide competition Genes to cells Medium 10971656
2001 ShcA expression in neural stem/progenitor cells promotes proliferation via Ras/MAPK and is downregulated as cells differentiate, whereupon ShcC takes over to support viability and neuronal maturation via PI3K-Akt-Bad pathway and persistent MAPK activation. The switch from ShcA to ShcC changes responsiveness from proliferative to survival/differentiation signaling. ShcC expression analysis, overexpression and functional assays in differentiating neural progenitor cells, PI3K/Akt pathway analysis Nature neuroscience Medium 11369938
2002 Shc p66 and p52 isoforms (but not p46) directly activate c-Src in an isoform-specific manner. Shc-c-Src interaction and c-Src autophosphorylation (activation segment) are demonstrated in vitro and in vivo. A Shc point mutant abolishing c-Src activation identified the interaction site. Shc-mediated c-Src activation triggers the Stat-p21/WAF1 pathway leading to cell cycle arrest. In vitro c-Src activation assay, co-immunoprecipitation, Shc point mutant that abolishes c-Src activation, isoform-specific analysis The Journal of biological chemistry High 12048194
2002 Serine phosphorylation of ShcA (Ser29 in p52; Ser138 in p66) by PKC isoforms (alpha, epsilon, delta) is required together with an intact PTB domain for ShcA binding to PTP-PEST. A PTP-PEST-binding-defective S29A ShcA mutant shows enhanced insulin-induced ERK activation and increased tyrosine phosphorylation, indicating PTP-PEST dephosphorylates ShcA to attenuate insulin signaling. Phosphorylation site mapping (mass spectrometry), PKC inhibitor and constitutively active PKC constructs, S29A/S138A mutants, co-immunoprecipitation, ERK activation assays The Journal of biological chemistry High 12052829
2002 ShcA (Shc) is essential for pre-TCR signaling in thymic T cell development: both inducible expression of phosphorylation-defective ShcA (dominant-negative) and conditional Shc locus deletion in thymocytes impaired pre-TCR signaling, proliferation, and differentiation at the same developmental stage. Cre-loxP conditional knockout, dominant-negative ShcA transgenic mice, T cell development stage analysis Nature immunology High 12101399
2002 ShcA is required for TCR-induced activation of c-Rel and IL-2 expression, but is dispensable for CD69/CD25 expression and NFAT activation. In Shc-deficient Jurkat cells, MAP kinase activation was impaired; rescue by exogenous Shc or c-Rel-ER fusion confirmed the pathway order: Shc → MAPK → c-Rel → IL-2. Shc-deficient Jurkat mutant cells, complementation with exogenous Shc, c-Rel-ER epistasis construct, reporter assays Proceedings of the National Academy of Sciences of the United States of America High 11917142
2002 DDR2 receptor tyrosine kinase requires Src activity for maximal tyrosine phosphorylation; Src promotes DDR2 association with Shc via a portion of Shc not previously implicated in RTK interactions. Src is required for DDR2-mediated MMP-2 promoter transactivation. Co-immunoprecipitation, Src kinase inhibition/knockdown, MMP-2 reporter assays The Journal of biological chemistry Medium 11884411
2002 E2 (estrogen) rapidly induces Shc phosphorylation and Shc-Grb2-Sos complex formation in MCF-7 cells. ERalpha and Src act upstream of Shc. Direct physical association between ERalpha and Shc is demonstrated by GST-Shc pulldown; the ShcA PTB and SH2 domains are required to interact with the ERalpha AF-1 domain. Dominant-negative Shc blocks E2-induced MAPK activation. GST-Shc pulldown, co-immunoprecipitation, Shc domain mutagenesis, dominant-negative Shc, inhibitor studies, confocal microscopy Molecular endocrinology High 11773443
2007 Upon TGF-beta stimulation, the activated TGF-beta type I receptor (TbetaRI) directly recruits and phosphorylates ShcA on both tyrosine and serine residues, using an intrinsic TbetaRI tyrosine kinase activity (dual-specificity kinase). ShcA phosphorylation induces ShcA-Grb2-Sos association, activating the Erk MAP kinase pathway independently of Smad signaling. In vitro TbetaRI kinase assays, tyrosine kinase-dead and serine-kinase-dead TbetaRI mutants, co-immunoprecipitation, Erk phosphorylation assays The EMBO journal High 17673906
2007 ShcA signals through combinatorial PTB-, SH2-, and pYXN-dependent interactions for distinct developmental functions: cardiomyocyte ShcA requires PTB but not pYXN motifs for mid-gestational heart development, whereas muscle spindle formation requires both pYXN and PTB/SH2 on the same ShcA molecule. Knock-in mice with domain-specific ShcA mutations (PTB-dead, pYXN mutants, combined mutants), histological and functional analysis of heart and muscle spindles Science High 17626887
2008 All three ShcA tyrosine phosphorylation sites (Y239/240, Y313) are involved in early mammary tumor progression. Y313-derived signals are important for tumor cell survival, whereas Y239/240 transduce signals promoting tumor vascularization. Loss of ShcA expression in mammary epithelial cells abrogates tumor development. Phosphotyrosine-deficient ShcA knock-in mice under endogenous promoter, mammary tumor progression analysis, histological and biochemical readouts The EMBO journal High 18273058
2008 In endothelial cells exposed to flow, Shc is activated and associates with cell-cell (VE-cadherin) and cell-matrix (integrin) adhesions. Shc activation requires VEGFR2 and Src tyrosine kinases. Shc-VE-cadherin association is matrix-independent; Shc-integrin binding requires VE-cadherin. Shc silencing reduces NF-kappaB-dependent inflammatory signaling and Shc is activated in atherosclerosis-prone arterial regions in vivo. Co-immunoprecipitation under flow conditions, siRNA knockdown, NF-kappaB reporter assay, in vivo arterial Shc activation analysis, dominant-negative Src/VEGFR2 The Journal of cell biology High 18606845
2009 14-3-3zeta is phosphorylated on Tyr179 in response to GM-CSF and binds the ShcA SH2 domain, assembling a 14-3-3:Shc scaffold that recruits PI3K to regulate Akt activation and cell survival. Y179F 14-3-3 fails to support Akt phosphorylation and viability in primary mast cells reconstituted with this mutant. Co-immunoprecipitation, 14-3-3zeta KO bone marrow mast cell reconstitution with WT vs. Y179F 14-3-3, Akt activation and viability assays The Journal of biological chemistry High 19218246
2010 The ShcA PTB domain directly interacts with a helical fragment from the IQGAP1 N-terminal region in a pTyr-independent, non-canonical manner (characterized by NMR). ShcA and IQGAP1 co-precipitate and are co-recruited to membrane ruffles induced by ErbB receptor activation. ShcA knockdown inhibits lamellipodia formation. ShcA PTB binding to IQGAP1 is mutually exclusive with binding to PTP-PEST peptide. NMR structural characterization, mass spectrometry, co-immunoprecipitation, siRNA knockdown, live-cell imaging of membrane ruffles The EMBO journal High 20075861
2010 p66(Shc) acts as a focal-adhesion-associated reporter of cell attachment. p66(Shc)-null cells show unrestrained Ras activation upon detachment, blocking anoikis. Re-expression of p66(Shc) in metastatic cells (which lack both p66Shc and pRB) restores anoikis and suppresses metastasis in vivo. p66(Shc) coordinates Ras-dependent control of proliferation and anchorage. Re-expression of p66(Shc) in p66-null metastatic cells, Ras activity assays, anoikis assays, in vivo metastasis models, p66(Shc) and pRB knockdown Oncogene High 20676142
2011 LRP1 forms a complex with the IGF-1 receptor and is required for ShcA tyrosine phosphorylation and membrane translocation in response to IGF-1. ShcA presence directs IGF-1 signaling toward Ras/MAP kinase; in the absence of ShcA, IGF-1 signaling bifurcates to Akt/mTOR, accelerating adipocyte differentiation. Co-immunoprecipitation, LRP1/ShcA siRNA knockdown, membrane fractionation, Ras/MAPK and Akt/mTOR activation assays, adipogenesis assays The Journal of biological chemistry High 21454706
2013 Shc1 responds to EGF stimulation through multiple sequential phosphorylation events and protein interactions: an initial wave recruits Grb2 to Shc1 pTyr sites, activating pro-mitogenic/survival pathways; Akt-mediated feedback then phosphorylates Shc1 Ser29, recruiting the Ptpn12 tyrosine phosphatase; Ptpn12 then acts as a switch converting Shc1 from pTyr/Grb2-based signaling to SgK269-mediated cytoskeletal/trafficking pathways regulating cell invasion. Quantitative mass spectrometry of Shc1 complexes over time, phosphomutant analysis, Ptpn12 co-IP, cell invasion and morphogenesis assays Nature High 23846654
2015 p52ShcA competes with Smad3 for TGF-beta receptor binding, sequesters TGF-beta receptor complexes to caveolin-associated membrane compartments (preventing clathrin-dependent Smad activation), and thereby protects epithelial cells from TGF-beta-induced EMT. ShcA knockdown enhances receptor localization in clathrin compartments, increases Smad3 activation, and induces EMT with increased migration, invasion, and stem cell generation. Co-immunoprecipitation, compartment fractionation (caveolin vs. clathrin), ShcA siRNA knockdown, Smad3 activation assays, EMT and invasion assays, mammosphere formation PLoS biology High 26680585
2016 DDR1b-mediated collagen I-induced N-cadherin upregulation requires Shc1 binding to DDR1b Tyr513 via its PTB domain. The signaling does not require the Shc1 SH2 domain or pY239/240/313 but requires a segment of the Shc1 central domain interacting with the proline-rich region of Pyk2, positioning Shc1 as a scaffold coupling DDR1b and Pyk2. Shc1 knockdown, PTB-domain mutants, SH2-domain mutants, pY mutants, Y513F DDR1b mutant, domain-specific interaction assays The Journal of biological chemistry High 27605668
2017 ShcA simultaneously activates STAT3 immunosuppressive signals and impairs STAT1-driven immune surveillance in breast cancer cells. Impaired Y239/Y240-ShcA phosphorylation selectively reduces STAT3 activation in tumors, sensitizing them to immune checkpoint inhibitors. pY-deficient ShcA knock-in mouse models, STAT3 and STAT1 activation assays, immune checkpoint immunotherapy experiments Nature communications High 28276425
2017 ShcA associates with nephrin (a podocyte slit diaphragm protein) via its SH2 domain binding to multiple phosphorylated tyrosine residues on nephrin. ShcA overexpression promotes nephrin tyrosine phosphorylation, reduces nephrin cell-surface expression, and decreases nephrin signaling. In a rat injury model, phospho-nephrin colocalizes with endocytic structures coincident with ShcA upregulation. Co-immunoprecipitation, GST pulldown, ShcA overexpression, in vivo biotinylation assay for surface vs. cytosolic nephrin, rat injury model Journal of the American Society of Nephrology High 29018139
2018 In endothelial cells, SHC1 recruits the PP2A scaffolding subunit to the proline-rich apoER2 C-terminus along with two distinct PP2A regulatory subunits in response to antiphospholipid antibodies (aPL), enabling inhibitory dephosphorylation of Akt and eNOS and promoting thrombosis. This was demonstrated by aPL-induced assembly of the apoER2/Dab2/SHC1/PP2A complex. Co-immunoprecipitation of apoER2-Dab2-SHC1-PP2A complex, SHC1 knockdown, Akt and eNOS phosphorylation assays, in vivo thrombosis model Blood High 29500169
2019 Genetic ablation of the p52SHC isoform (but not p66SHC) significantly attenuates DMBA-induced mammary tumor formation in rats, identifying p52SHC as the oncogenic isoform driving breast cancer initiation. p52SHC KO disrupted ESR1 and mTORC2/RICTOR pathway gene networks. Germline isoform-specific p52SHC and p66SHC knockout rats, DMBA mammary tumor induction model, RNA-seq, gene network analysis Breast cancer research High 31202267
2021 Endothelial Shc acts downstream of the mechanoreceptor Alk5 to mediate shear-stress-induced endothelial-to-mesenchymal transition (EndMT) and atherosclerosis. Genetic targeting of endothelial Shc reduces EndMT and atherosclerosis in areas of disturbed flow. Alk5-mediated mechanosensing drives Shc activation independently of other mechanosensors. Endothelial-specific Shc genetic targeting (in vivo), Alk5 depletion, reconstitution experiments with tensional force, atherosclerosis model Science advances High 34244146
2003 ShcA (via its SH2 domain) binds Tyr1101 of the Tie2 receptor following angiopoietin-1 stimulation, leading to Shc phosphorylation. Dominant-negative ShcA impairs angiopoietin-1-induced endothelial chemotaxis and sprouting (but not survival) and partially reduces PI3K p85 tyrosine phosphorylation. In vitro co-immunoprecipitation, pulldown with Tie2 phosphopeptides, overexpression of dominant-negative ShcA, chemotaxis and sprouting assays The Journal of biological chemistry Medium 14665640
2010 Chlamydia trachomatis effector protein Tarp interacts with SHC1 as one of its strongest binding partners (demonstrated by phosphopeptide-SH2/PTB domain protein array). SHC1 knockdown in C. trachomatis-infected cells sensitizes them to TNF-induced apoptosis, identifying SHC1-dependent regulation of apoptosis-related genes as important for early chlamydial infection survival. Protein microarray of all human SH2/PTB domains, quantitative binding measurements, SHC1 siRNA knockdown, apoptosis assay, transcriptome analysis The Journal of cell biology Medium 20624904
2014 p66(Shc) is phosphorylated at Ser36 in response to pathological cyclic stretch in endothelial cells, downstream of integrin alpha5beta1 and c-Jun N-terminal kinase. This phosphorylation activates NADPH oxidase, increases ROS production, and reduces nitric oxide bioavailability. Silencing p66(Shc) blunts these stretch-induced effects. Cyclic stretch of primary human aortic endothelial cells, integrin inhibition, JNK inhibition, p66(Shc) siRNA knockdown, ROS and NADPH oxidase assays, NO bioavailability measurements Hypertension High 24842918
2018 Idebenone physically binds Shc protein (p52 isoform) and inhibits Shc's competition with IRS1 downstream of the insulin receptor. Genetic depletion of Shc's target eliminates idebenone's ability to insulin-sensitize in vivo. Multiple target-engagement assays confirm direct idebenone-Shc binding. In vitro Shc binding assays (multiple orthogonal assays), p52Shc genetic depletion in mice, insulin sensitivity assays (two mouse models), drug screening of 1680 compounds Pharmacological research High 30290222

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1996 The adaptor protein Shc couples a class of integrins to the control of cell cycle progression. Cell 649 8929541
2007 TGF-beta activates Erk MAP kinase signalling through direct phosphorylation of ShcA. The EMBO journal 471 17673906
1999 Shc and FAK differentially regulate cell motility and directionality modulated by PTEN. The Journal of cell biology 368 10427092
2000 The TrkB-Shc site signals neuronal survival and local axon growth via MEK and P13-kinase. Neuron 363 10985347
2002 Linkage of rapid estrogen action to MAPK activation by ERalpha-Shc association and Shc pathway activation. Molecular endocrinology (Baltimore, Md.) 357 11773443
2001 Signaling via Shc family adapter proteins. Oncogene 344 11607835
1994 Compartmentalization of SHC, GRB2 and mSOS, and hyperphosphorylation of Raf-1 by EGF but not insulin in liver parenchyma. The EMBO journal 294 7925272
2013 Temporal regulation of EGF signalling networks by the scaffold protein Shc1. Nature 244 23846654
2000 New role for Shc in activation of the phosphatidylinositol 3-kinase/Akt pathway. Molecular and cellular biology 219 10982827
2012 Gene silencing of the mitochondrial adaptor p66(Shc) suppresses vascular hyperglycemic memory in diabetes. Circulation research 213 22693349
2007 Genetic deletion of p66(Shc) adaptor protein prevents hyperglycemia-induced endothelial dysfunction and oxidative stress. Proceedings of the National Academy of Sciences of the United States of America 203 17360381
2000 Evolution of Shc functions from nematode to human. Current opinion in genetics & development 177 11088019
1998 Requirement for both Shc and phosphatidylinositol 3' kinase signaling pathways in polyomavirus middle T-mediated mammary tumorigenesis. Molecular and cellular biology 176 9528804
1995 The motogenic and mitogenic responses to HGF are amplified by the Shc adaptor protein. Oncogene 171 7731718
1995 G protein-coupled chemoattractant receptors regulate Lyn tyrosine kinase.Shc adapter protein signaling complexes. The Journal of biological chemistry 158 7650013
2000 Distinct roles of the adaptor protein Shc and focal adhesion kinase in integrin signaling to ERK. The Journal of biological chemistry 151 10976102
1994 Direct interaction between Shc and the platelet-derived growth factor beta-receptor. The Journal of biological chemistry 147 8195171
2000 The ShcA phosphotyrosine docking protein sensitizes cardiovascular signaling in the mouse embryo. Genes & development 143 10809671
2019 LRP1 activation attenuates white matter injury by modulating microglial polarization through Shc1/PI3K/Akt pathway after subarachnoid hemorrhage in rats. Redox biology 136 30703614
1995 Growth hormone-promoted tyrosyl phosphorylation of SHC proteins and SHC association with Grb2. The Journal of biological chemistry 132 7535773
1994 Shc, Grb2, Sos1, and a 150-kilodalton tyrosine-phosphorylated protein form complexes with Fms in hematopoietic cells. Molecular and cellular biology 126 7520523
2008 ShcA signalling is essential for tumour progression in mouse models of human breast cancer. The EMBO journal 121 18273058
2013 MiR-365 induces gemcitabine resistance in pancreatic cancer cells by targeting the adaptor protein SHC1 and pro-apoptotic regulator BAX. Cellular signalling 115 24216611
1995 G protein beta gamma subunits stimulate phosphorylation of Shc adapter protein. Proceedings of the National Academy of Sciences of the United States of America 113 7568118
1996 Pathways downstream of Shc and Grb2 are required for cell transformation by the tpr-Met oncoprotein. The Journal of biological chemistry 110 8662733
1997 Identification of Shc docking site on Ret tyrosine kinase. Oncogene 107 9047384
2002 Discoidin domain receptor 2 interacts with Src and Shc following its activation by type I collagen. The Journal of biological chemistry 106 11884411
2001 Shc signaling in differentiating neural progenitor cells. Nature neuroscience 96 11369938
1998 Emerging roles for SH2/PTB-containing Shc adaptor proteins in the developing mammalian brain. Trends in neurosciences 91 9829689
1996 Interaction of Shc with adaptor protein adaptins. The Journal of biological chemistry 84 8617812
1995 MAP kinase phosphorylation of mSos1 promotes dissociation of mSos1-Shc and mSos1-EGF receptor complexes. Oncogene 81 7478566
1998 Shc and Enigma are both required for mitogenic signaling by Ret/ptc2. Molecular and cellular biology 78 9528800
2002 Isoform-specific knockdown and expression of adaptor protein ShcA using small interfering RNA. The Biochemical journal 76 11903040
1995 Erythropoietin-induced recruitment of Shc via a receptor phosphotyrosine-independent, Jak2-associated pathway. The Journal of biological chemistry 72 7538110
2012 Teaching an old dogma new tricks: twenty years of Shc adaptor signalling. The Biochemical journal 69 22970934
1995 Shc isoform-specific tyrosine phosphorylation by the insulin and epidermal growth factor receptors. The Journal of biological chemistry 69 7544794
2018 Antiphospholipid antibodies induce thrombosis by PP2A activation via apoER2-Dab2-SHC1 complex formation in endothelium. Blood 66 29500169
1997 Expression and activation of SH2/PTB-containing ShcA adaptor protein reflects the pattern of neurogenesis in the mammalian brain. Proceedings of the National Academy of Sciences of the United States of America 66 9223336
2021 Mechanical forces regulate endothelial-to-mesenchymal transition and atherosclerosis via an Alk5-Shc mechanotransduction pathway. Science advances 65 34244146
2008 Role of the life span determinant P66(shcA) in ethanol-induced liver damage. Laboratory investigation; a journal of technical methods and pathology 65 18490896
2010 Tarp regulates early Chlamydia-induced host cell survival through interactions with the human adaptor protein SHC1. The Journal of cell biology 63 20624904
1998 Insulin receptor substrate 2 and Shc play different roles in insulin-like growth factor I signaling. The Journal of biological chemistry 63 9852124
1999 Cloning and characterization of mPAL, a novel Shc SH2 domain-binding protein expressed in proliferating cells. Oncogene 61 10086341
1994 Activators of protein kinase C stimulate association of Shc and the PEST tyrosine phosphatase. The Journal of biological chemistry 61 7929214
1999 SHC and SHIP phosphorylation and interaction in response to activation of the FLT3 receptor. Leukemia 58 10482988
2017 The Shc1 adaptor simultaneously balances Stat1 and Stat3 activity to promote breast cancer immune suppression. Nature communications 57 28276425
2016 Up-regulation of N-cadherin by Collagen I-activated Discoidin Domain Receptor 1 in Pancreatic Cancer Requires the Adaptor Molecule Shc1. The Journal of biological chemistry 57 27605668
2002 Adaptor protein Shc is an isoform-specific direct activator of the tyrosine kinase c-Src. The Journal of biological chemistry 57 12048194
2007 Combinatorial ShcA docking interactions support diversity in tissue morphogenesis. Science (New York, N.Y.) 54 17626887
2003 p66(Shc): at the crossroad of oxidative stress and the genetics of aging. Trends in molecular medicine 54 12763525
2010 p66(Shc) restrains Ras hyperactivation and suppresses metastatic behavior. Oncogene 53 20676142
1997 Shc mediates IL-6 signaling by interacting with gp130 and Jak2 kinase. Journal of immunology (Baltimore, Md. : 1950) 52 9126968
2000 Involvement of Shc and Cbl-PI 3-kinase in Lyn-dependent proliferative signaling pathways for G-CSF. Oncogene 51 10644984
2005 Expression of p66(Shc) protein correlates with proliferation of human prostate cancer cells. Oncogene 50 16170380
1997 Interaction of the adaptor protein Shc and the adhesion molecule cadherin. The Journal of biological chemistry 50 9153187
2007 Analysis of a Shc family adaptor protein, ShcD/Shc4, that associates with muscle-specific kinase. Molecular and cellular biology 49 17452444
2009 p66(Shc) protein, oxidative stress, and cardiovascular complications of diabetes: the missing link. Journal of molecular medicine (Berlin, Germany) 48 19590843
2008 Shc coordinates signals from intercellular junctions and integrins to regulate flow-induced inflammation. The Journal of cell biology 47 18606845
2004 The role of adapter protein Shc in estrogen non-genomic action. Steroids 46 15288764
2014 Adaptor protein p66(Shc) mediates hypertension-associated, cyclic stretch-dependent, endothelial damage. Hypertension (Dallas, Tex. : 1979) 45 24842918
2005 p66(shc) is highly expressed in fibroblasts from centenarians. Mechanisms of ageing and development 45 15992607
2002 Serine/threonine phosphorylation of ShcA. Regulation of protein-tyrosine phosphatase-pest binding and involvement in insulin signaling. The Journal of biological chemistry 44 12052829
2000 Adaptor protein Shc undergoes translocation and mediates up-regulation of the tyrosine kinase c-Src in EGF-stimulated A431 cells. Genes to cells : devoted to molecular & cellular mechanisms 44 10971656
2015 ShcA Protects against Epithelial-Mesenchymal Transition through Compartmentalized Inhibition of TGF-β-Induced Smad Activation. PLoS biology 43 26680585
2008 Genetic variation in candidate obesity genes ADRB2, ADRB3, GHRL, HSD11B1, IRS1, IRS2, and SHC1 and risk for breast cancer in the Cancer Prevention Study II. Breast cancer research : BCR 43 18611262
2001 ShcA and Grb2 mediate polyoma middle T antigen-induced endothelial transformation and Gab1 tyrosine phosphorylation. The EMBO journal 43 11707404
2006 Mitochondrial DNA copy number is regulated by cellular proliferation: a role for Ras and p66(Shc). Biochimica et biophysica acta 42 16829231
2005 Hippocampal synaptic modulation by the phosphotyrosine adapter protein ShcC/N-Shc via interaction with the NMDA receptor. The Journal of neuroscience : the official journal of the Society for Neuroscience 42 15716419
2002 A nonredundant role for the adapter protein Shc in thymic T cell development. Nature immunology 41 12101399
2019 The p52 isoform of SHC1 is a key driver of breast cancer initiation. Breast cancer research : BCR 40 31202267
2015 The p66(Shc) redox adaptor protein is induced by saturated fatty acids and mediates lipotoxicity-induced apoptosis in pancreatic beta cells. Diabetologia 39 25810038
2003 Adaptor ShcA protein binds tyrosine kinase Tie2 receptor and regulates migration and sprouting but not survival of endothelial cells. The Journal of biological chemistry 39 14665640
2013 The p66(Shc) gene paves the way for healthspan: evolutionary and mechanistic perspectives. Neuroscience and biobehavioral reviews 37 23524280
1999 Bifurcation of cell migratory and proliferative signaling by the adaptor protein Shc. The Journal of cell biology 37 10613912
2016 P66Shc-SIRT1 Regulation of Oxidative Stress Protects Against Cardio-cerebral Vascular Disease. Molecular neurobiology 32 27578018
2014 p66(Shc)-induced redox changes drive endothelial insulin resistance. Atherosclerosis 32 25150941
2009 Positive and negative regulation of antigen receptor signaling by the Shc family of protein adapters. Immunological reviews 32 19909360
2002 The ShcA protein is a molecular chaperone that assists in the secretion of the HopPsyA effector from the type III (Hrp) protein secretion system of Pseudomonas syringae. Molecular microbiology 32 12067337
2020 DEPDC1B is a tumor promotor in development of bladder cancer through targeting SHC1. Cell death & disease 31 33203836
2009 14-3-3:Shc scaffolds integrate phosphoserine and phosphotyrosine signaling to regulate phosphatidylinositol 3-kinase activation and cell survival. The Journal of biological chemistry 31 19218246
2007 ALK activation induces Shc and FRS2 recruitment: Signaling and phenotypic outcomes in PC12 cells differentiation. FEBS letters 31 17274988
2020 PTRF/CAVIN1, regulated by SHC1 through the EGFR pathway, is found in urine exosomes as a potential biomarker of ccRCC. Carcinogenesis 30 31605605
2014 The p66(Shc) adaptor protein controls oxidative stress response in early bovine embryos. PloS one 30 24475205
2008 The ShcA adaptor protein is a critical regulator of breast cancer progression. Cell cycle (Georgetown, Tex.) 30 18604176
2008 A novel role of Shc adaptor proteins in steroid hormone-regulated cancers. Endocrine-related cancer 29 19001530
2004 The insulin-like growth factor-1 pathway mediator genes: SHC1 Met300Val shows a protective effect in breast cancer. Carcinogenesis 29 15308584
2018 Activated protein C reverses epigenetically sustained p66Shc expression in plaque-associated macrophages in diabetes. Communications biology 28 30271984
2012 Genetic inactivation of the p66 isoform of ShcA is neuroprotective in a murine model of multiple sclerosis. The European journal of neuroscience 28 22277070
2006 Neural-specific inactivation of ShcA results in increased embryonic neural progenitor apoptosis and microencephaly. The Journal of neuroscience : the official journal of the Society for Neuroscience 28 16870734
2002 Genetic evidence for Shc requirement in TCR-induced c-Rel nuclear translocation and IL-2 expression. Proceedings of the National Academy of Sciences of the United States of America 28 11917142
2018 Idebenone is a cytoprotective insulin sensitizer whose mechanism is Shc inhibition. Pharmacological research 26 30290222
1999 Neuregulin-increased expression of acetylcholine receptor epsilon-subunit gene requires ErbB interaction with Shc. Journal of neurochemistry 26 10582594
1999 Role of tyrosine residues and protein interaction domains of SHC adaptor in VEGF receptor 3 signaling. Oncogene 26 9927207
1994 Chromosome locations of genes encoding human signal transduction adapter proteins, Nck (NCK), Shc (SHC1), and Grb2 (GRB2). Genomics 26 7806213
2017 ShcA Adaptor Protein Promotes Nephrin Endocytosis and Is Upregulated in Proteinuric Nephropathies. Journal of the American Society of Nephrology : JASN 25 29018139
2016 The redox protein p66(shc) mediates cochlear vascular dysfunction and transient noise-induced hearing loss. Scientific reports 25 27157635
2012 Targeting MCT-1 oncogene inhibits Shc pathway and xenograft tumorigenicity. Oncotarget 24 23211466
2011 Differential signaling by adaptor molecules LRP1 and ShcA regulates adipogenesis by the insulin-like growth factor-1 receptor. The Journal of biological chemistry 24 21454706
2013 Feedback loop between p66(Shc) and Nrf2 promotes lung cancer progression. Cancer letters 23 23689140
2010 The PTB domain of ShcA couples receptor activation to the cytoskeletal regulator IQGAP1. The EMBO journal 22 20075861

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