| 1996 |
GAB1 interacts directly with the c-Met receptor tyrosine kinase via a proline-rich Met-binding domain (not related to known phosphotyrosine-binding domains); this interaction is specific to c-Met among tested tyrosine kinases. Expression of GAB1 in epithelial cells is sufficient to induce c-Met-specific branching morphogenesis. |
Co-immunoprecipitation, domain mapping, cell-based morphogenesis assay |
Nature |
High |
8906793
|
| 1997 |
Association of GAB1 with the Met/HGF receptor requires a functional Grb2 binding site at tyrosine 1356 (and to a lesser extent Y1349) in the receptor C-terminus; Met receptor mutants impaired in Grb2/GAB1 recruitment fail to induce branching tubulogenesis. GAB1 is the major substrate for the Met kinase in vitro and in vivo. |
In vitro kinase assay, co-immunoprecipitation with receptor mutants, tubulogenesis assay in MDCK cells |
The Journal of biological chemistry |
High |
9252406 9444958
|
| 1997 |
GAB1 coupling to the Met receptor requires prior binding of Grb2 (both SH2 and SH3 domain-blocking peptides interfere with receptor–GAB1 interaction). GAB1 phosphorylation by Met correlates with the transforming potential of oncogenic Tpr-Met. |
Point mutations in Met docking site, SH2/SH3 blocking peptides, co-immunoprecipitation, transformation assay |
Oncogene |
High |
9444958
|
| 1998 |
GAB1 is tyrosine-phosphorylated in response to IL-6, IL-3, IFN-α, and IFN-γ. Upon IL-6/IL-3 stimulation, GAB1 forms a complex with PI3K and SHP-2. GAB1 overexpression enhances gp130-dependent ERK2 activation; this requires tyrosine 759 (the SHP-2 binding site of gp130) and involves PI3K and Ras. |
Co-immunoprecipitation, dominant-negative PI3K expression, wortmannin inhibition, ERK2 kinase assay |
Molecular and cellular biology |
High |
9632795
|
| 1998 |
GAB1 is phosphorylated by the insulin receptor (IR) on tyrosine residues; Y472 is the major site for association with p85 (PI3K), with Y447 and Y589 also participating. Y627 is the primary site for SHP-2 SH2 domain binding. The GAB1 PH domain is not required for IR/GAB1 interaction in vitro but is crucial for tyrosine phosphorylation and SHP-2 association in intact cells. |
Modified yeast two-hybrid, in vitro phosphorylation/pull-down, site-directed mutagenesis |
Molecular endocrinology |
High |
9658397
|
| 1999 |
The GAB1 PH domain binds PtdIns(3,4,5)P3 specifically and mediates GAB1 translocation to the plasma membrane in response to EGF; this translocation is required for efficient GAB1 tyrosine phosphorylation. A positive feedback loop exists in which PI3K is both upstream (generating PtdIns(3,4,5)P3 to recruit GAB1 via PH domain) and downstream (activated by phospho-GAB1) effector. PTEN overexpression inhibits EGF signaling and GAB1 membrane translocation. |
PH domain–lipid binding assay (PtdIns specificity), membrane translocation by subcellular fractionation/imaging, dominant-interfering PI3K mutant, PTEN overexpression, mutant Gab1 rescue experiments |
Molecular and cellular biology |
High |
10648629
|
| 1999 |
The GAB1 PH domain is required for localization of GAB1 at sites of cell–cell contact and for PI3K-dependent epithelial tubulogenesis downstream from the Met receptor. PH-domain deletion causes cytoplasmic mislocalization. LY294002 (PI3K inhibitor) blocks GAB1 membrane localization. |
Confocal imaging of GFP-tagged GAB1 constructs, LY294002 treatment, tubulogenesis assay with rescue experiments |
Molecular and cellular biology |
High |
10022866
|
| 1999 |
In response to EGF receptor (EGFR) stimulation, GAB1 associates with the EGFR in vivo and in vitro via phosphotyrosines 1068 and 1086 in the EGFR C-terminal tail. GAB1 overexpression potentiates EGF-induced MAPK and JNK activation in a manner requiring PI3K binding. |
Co-immunoprecipitation (in vivo and in vitro), receptor mutant analysis, PI3K dominant-interfering mutant, wortmannin treatment |
Molecular and cellular biology |
High |
10648629
|
| 1999 |
EGFR phosphorylates GAB1 at eight tyrosine residues in vitro (Y285, Y373, Y406, Y447, Y472, Y619, Y657, Y689); Y657 is the predominant phosphorylation site and a specific binding site for SHP-2/Syp, as shown by GST pull-down with Y657F mutant abrogating binding. |
In vitro EGFR kinase assay, phosphopeptide mapping by HPLC/Edman/MS, GST pull-down with cell lysates |
Biochemistry |
High |
9890893
|
| 1999 |
GAB1 associates with CRKL via the CRKL SH2 domain and GAB1 YXXP motifs after HGF stimulation; CRKL then engages C3G (via CRKL SH3 domain) to activate the small GTPase Rap1. A GabΔYXXP mutant abolishes HGF-induced Rap1 activation, identifying a HGF→GAB1→CRKL→C3G→Rap1 signaling pathway. |
Co-immunoprecipitation, dominant-negative C3G truncation, Rap1 activation assay, GAB1 YXXP mutant |
The Journal of biological chemistry |
High |
10753869
|
| 1999 |
GAB1 mediates NGF-independent neurite outgrowth, DNA synthesis, and cell survival in PC12 cells. Constitutively phosphorylated GAB1 induces Akt and MAPK activation; neuritogenesis is abolished by MEK inhibition and partially by PI3K inhibition; survival requires both PI3K and MEK pathways. |
Recombinant adenovirus-driven GAB1 expression, pharmacological inhibitors (MEK, PI3K), neurite outgrowth assay, MTT survival assay |
The Journal of biological chemistry |
Medium |
10601297
|
| 1999 |
GAB1 is tyrosine-phosphorylated by erythropoietin (EPO) receptor activation and subsequently associates with PI3K (p85), SHP2, SHIP, and SHC; GAB1–Grb2 association increases upon EPO stimulation. GAB1 is the primary IRS-related protein activated by EPO in primary erythroid progenitors. |
Co-immunoprecipitation, EPO dose-response/time-course phosphorylation, primary cell analysis |
Blood |
Medium |
10194437
|
| 2000 |
The c-Met binding site on GAB1 is localized to a 13-amino acid region unique to GAB1; insertion of this region into Gab2 confers c-Met binding activity. Two Grb2 binding sites were mapped: a classical PXXP motif and a novel PX(V/I)(D/N)RXXKP motif. Association of GAB1 with SHP2 (not PI3K, CRKL, or Shc) is essential for HGF/Met-induced branching morphogenesis in MDCK cells. |
Reverse yeast two-hybrid technology, phosphorylation-dependent yeast two-hybrid, domain swapping (Gab2 chimera), MDCK branching morphogenesis assay |
The Journal of cell biology |
High |
10871282
|
| 2000 |
GAB1-deficient embryos die in utero with defects in heart, placenta, and skin, and show severely reduced ERK MAPK activation in response to HGF, PDGF, EGF, and gp130 stimulation, establishing GAB1 as a common adapter for ERK activation by multiple growth factors and cytokines in vivo. |
Gab1 gene targeting (knockout mice), ERK activation assay in embryonic cells, phenotypic analysis |
Molecular and cellular biology |
High |
10779359
|
| 2000 |
Gab1 is essential for c-Met signaling in vivo: Gab1−/− mice phenocopy c-Met mutants in muscle progenitor migration defects (absent forelimb extensor muscles, diaphragm muscle loss), liver size reduction, and placental labyrinth defects. Gab1−/−;c-Met+/− compound mutants show enhanced muscle migration defects, providing genetic epistasis evidence that GAB1 is essential for c-Met signaling. |
Targeted mutagenesis in mouse, genetic epistasis (double mutant analysis), histological phenotypic analysis |
The Journal of cell biology |
High |
10995442
|
| 2000 |
CXCR4 and GAB1 interact genetically in migrating muscle progenitor development: muscle progenitors fail to reach the tongue anlage in CXCR4;Gab1 double mutants but colonize this target in either single mutant, demonstrating cooperative/synergistic genetic interaction. |
Double-mutant mouse analysis, genetic epistasis |
Genes & development |
Medium |
16166380
|
| 2001 |
Phosphotyrosines 627 and 659 of GAB1 constitute a bisphosphoryl tyrosine-based activation motif (BTAM) that binds SHP2 tandem SH2 domains in a specific orientation (N-SH2→pY627, C-SH2→pY659) and activates SHP2 phosphatase activity. GAB1 is also a substrate of SHP2 (dephosphorylated by SHP2 in vitro and confirmed by substrate-trapping in cells). Physical association of active SHP2 with GAB1 (not just SHP2 activity alone) is necessary and sufficient for ERK2 activation. |
Far Western blot (tandem SH2 orientation), in vitro SHP2 phosphatase assay with bisphosphopeptides, substrate-trapping with catalytically inactive SHP2, chimeric Gab1FF-SHP2ΔN rescue |
The Journal of biological chemistry |
High |
11323411
|
| 2001 |
Activated ERK2 directly associates with GAB1 via the Met-binding domain (MBD) exclusively in its phosphorylated form; GAB1 is an ERK2 substrate in vitro and shows increased serine phosphorylation in cells co-expressing constitutively active MEK1. ERK-mediated phosphorylation of GAB1 at a threonine adjacent to the pY472 site (pYT peptide) increases affinity for p85 PI3K, providing positive feedback (HGF context). |
GST pull-down with purified pERK2 vs non-pERK2, co-immunoprecipitation in intact cells, in vitro kinase assay, phosphopeptide competition/pull-down assay |
The Journal of biological chemistry |
High |
10593929 11445578
|
| 2001 |
ERK negatively regulates GAB1 tyrosine phosphorylation and GAB1/PI3K interaction in the EGF (but not HGF) context: MEK inhibition by U0126 increases EGF-stimulated GAB1 tyrosine phosphorylation, SHP2 association, and GAB1/p85 association and PI3K/Akt activation. SHP2 dephosphorylates GAB1, suggesting EGF-stimulated ERK acts through SHP2 to reduce GAB1 phosphorylation. |
MEK inhibitor (U0126), co-immunoprecipitation, GST-p85 pull-down, pervanadate treatment, dominant-negative SHP2 |
The Journal of biological chemistry |
Medium |
11896055
|
| 2001 |
PKC-α and PKC-β1 mediate serine/threonine hyperphosphorylation of GAB1 (upon PP1/PP2A inhibition by okadaic acid), which suppresses GAB1 tyrosine phosphorylation and its recruitment of PI3K, providing a negative-feedback mechanism for HGF/Met receptor signaling. |
Okadaic acid treatment, PKC isoform-specific inhibitors/activators, co-immunoprecipitation, phosphoamino acid analysis |
Oncogene |
Medium |
11313945
|
| 2001 |
ERK regulates the HGF-mediated GAB1/PI3K interaction positively: ERK inhibition reduces HGF-stimulated association of Gab1 with p85 and decreases Akt activation; a phosphothreonine+phosphotyrosine (pYT) peptide at the GAB1 YVPM motif shows higher affinity for p85 than phosphotyrosine alone, indicating ERK-phosphorylated threonine at T476 augments PI3K recruitment. |
MEK inhibitor, GST-p85 pull-down, co-immunoprecipitation, synthetic pY and pYT peptide competition assays |
The Journal of biological chemistry |
High |
11445578
|
| 2001 |
GAB1 forms complexes with p85 PI3K and SHP2 upon Met transformation; Crk associates with Gab1 (not p130Cas/paxillin) in Met-transformed cells and in suspension-grown cells, and Gab1-Crk coupling activates JNK in anchorage-independent conditions. |
Co-immunoprecipitation in adherent and suspension conditions, JNK activation assay |
Oncogene |
Medium |
11146548
|
| 2002 |
GAB1 recruits SHP2 to dephosphorylate paxillin, causing dissociation of Csk from paxillin, which dephosphorylates Src Y530 and activates Src. This Gab1→SHP2→paxillin dephosphorylation→Src activation pathway is required for EGF-induced ERK activation and cell migration; SHP2-binding-defective Gab1FF blocks all these events. |
Co-immunoprecipitation, SHP2 substrate assay (paxillin dephosphorylation in vitro and in cells), Src Y530 phosphorylation analysis, cell migration assay, dominant-negative SHP2 |
The Journal of biological chemistry |
High |
14665621
|
| 2002 |
GAB1 and SHP2 promote Ras/MAPK activity in epidermis: Gab1-deficient epidermis shows lower active Ras and MAPK levels; Gab1Y627F (SHP2-binding-defective) reduces basal Ras and triggers differentiation; these effects are rescued by active Ras, placing GAB1/SHP2 upstream of Ras. |
Gab1−/− mouse epidermis, dominant-negative SHP2, Gab1Y627F mutant, activated Ras rescue, human epidermis organotypic culture |
The Journal of cell biology |
High |
12370245
|
| 2002 |
IGF-1 downregulates GAB1 expression in endothelial cells; GAB1 associates with MEKK3 and inhibits MEKK3-induced c-Jun and NF-κB transcriptional activation; catalytically inactive MEKK3 also inhibits TNF-α-induced c-Jun and NF-κB activation, implicating the GAB1-MEKK3 complex in TNF-α signaling. |
Co-immunoprecipitation (Gab1-MEKK3), reporter assays (c-Jun, NF-κB), dominant-negative MEKK3, Western blot for Gab1 expression |
Circulation research |
Medium |
12065326
|
| 2003 |
Met-activated Gab1 directly interacts with cortactin via Gab1 proline-rich motifs P4/5 and the cortactin SH3 domain; this Gab1-cortactin complex is required for Met-mediated invadopodia formation and cell invasion. Uncoupling cortactin from Gab1 (via P4/5 mutations) abrogates invadopodia and invasion. |
Gab1-null fibroblasts, Gab1 siRNA in tumor cells, structure-function (P4/5 deletion mutants), direct interaction assay (cortactin SH3 pull-down), invadopodia assay, invasion assay |
Journal of cell science |
High |
22366451
|
| 2003 |
Grb2-independent recruitment of Gab1 to Met requires a 16-amino acid motif within the Gab1 Met-binding domain (MBD) and the structural integrity of the Met kinase domain C-terminal lobe including residues upstream of pY1349; substitution of Y1349 with an acidic residue (phosphomimetic) allows Gab1 MBD recruitment and Gab1 phosphorylation. |
Met kinase domain mutants, deletion mapping of Gab1 MBD (16-aa minimal motif), co-immunoprecipitation, in vitro binding |
The Journal of biological chemistry |
Medium |
12766170
|
| 2004 |
ERK1/2 phosphorylates GAB1 at six serine/threonine residues (T312, S381, S454, T476, S581, S597) in vitro; S454, S581, S597, T476 account for ~80% of incorporated phosphate. These ERK phosphorylation sites are located adjacent to PI3K-binding YVPM motifs and their phosphorylation blocks PI3K and Akt activity in intact cells (insulin signaling context). |
In vitro ERK1/2 kinase assay, 2D-HPLC phosphopeptide mapping, MALDI-MS + Edman sequencing, PI3K/Akt activity assays in cells |
Biochemistry |
High |
15379552
|
| 2004 |
EGF ligand binding increases EGFR kinase affinity (lowers Km ~4-6-fold) for Gab1 Y627 and Shc Y317 peptides while increasing kcat ~5-fold for all peptides, resulting in ~15–40-fold increase in specificity constants for these substrates vs ~5-fold for EGFR autophosphorylation sites. EGF significantly enhances Gab1 Y627 and Shc Y317 phosphorylation relative to EGFR autophosphorylation in cell lysates. |
Steady-state enzyme kinetics with synthetic peptides, purified EGFR, GST fusion protein binding assay, cell lysate phosphorylation comparison |
The Journal of biological chemistry |
High |
15231819
|
| 2004 |
Noonan syndrome SHP2 mutants show increased basal phosphatase activity and prolonged, EGF-dependent binding to GAB1 with sustained tyrosine phosphorylation of both proteins. Coexpression of Gab1-FF (lacking SHP2 binding motifs) blocks EGF-mediated increase in SHP2 phosphatase activity and dramatically reduces ERK2 activation, demonstrating that docking through GAB1 is required for Noonan syndrome SHP2 mutant-driven sustained ERK2 activation. |
Phosphatase activity assay, co-immunoprecipitation time-course, Gab1-FF dominant-negative, ERK2 activation assay, cell proliferation assay |
Human mutation |
High |
14974085
|
| 2004 |
GAB1 is the primary mediator of EGF-stimulated PI3K/Akt activation: Gab1−/− MEFs show severely impaired EGF-induced PI3K and Akt activation; three canonical GAB1 tyrosine phosphorylation sites mediate p85 complex formation. SHP2 association with GAB1 negatively regulates GAB1-mediated PI3K/Akt activation following EGFR stimulation. |
Gab1−/− MEFs, rescue with GAB1 mutants, PI3K assay, Akt phosphorylation, co-immunoprecipitation |
BMC biology |
High |
15550174
|
| 2004 |
SHP2 dephosphorylates YXXP motifs on GAB1 (including Y317-containing motif) to prevent RasGAP binding; when SHP2 is inactive, RasGAP binds phospho-Y317 on GAB1, relocates to the membrane, and inhibits Ras. A RasGAP-inactive mutant restores Ras activation in SHP2-deficient or Gab1-SHP2-binding-defective cells. GAB1 interacts with RasGAP SH2 domains via pY317. |
Substrate-trapping SHP2 mutant, Gab1 YXXP deletion mutant, RasGAP-inactive mutant rescue, RasGAP relocalization by fractionation, Ras activation assay |
The Journal of biological chemistry |
High |
15574420
|
| 2005 |
Laminar flow-induced GAB1 tyrosine phosphorylation is Src kinase-dependent and VEGFR2-dependent; phospho-GAB1 associates with p85 PI3K; a GAB1 mutant lacking p85 binding sites or Gab1 siRNA knockdown inhibits flow-induced Akt and eNOS activation. |
Src inhibitor PP2, VEGFR2 kinase inhibitors, co-immunoprecipitation, siRNA knockdown, Akt/eNOS phosphorylation assay |
The Journal of biological chemistry |
Medium |
15665327
|
| 2005 |
Fluid shear stress-induced eNOS activation depends on GAB1-SHP2 interaction: mutation of GAB1 Y627F prevents shear-induced eNOS phosphorylation (but not Akt); dominant-negative SHP2 prevents PKA activation and eNOS phosphorylation. GAB1, SHP2, eNOS, and PKA catalytic subunit form a signalosome complex under shear. GAB1 PH domain is required for shear-induced Akt phosphorylation but not eNOS activation. |
GAB1 Y627F mutant, dominant-negative SHP2, co-immunoprecipitation of signalosome, PKA inhibitor, isolated murine carotid arteries (ex vivo validation) |
Circulation research |
High |
16284184
|
| 2005 |
Hck (hematopoietic cell kinase), a Src family kinase, phosphorylates GAB1 and GAB2 in response to IL-6 in multiple myeloma cells; PP2 (Src family inhibitor) and kinase-inactive Hck mutants reduce IL-6-triggered GAB1 tyrosine phosphorylation, ERK activation, and Akt activation, impairing myeloma cell proliferation and survival. |
Kinase-inactive Hck mutant expression, Src family kinase inhibitor PP2, co-immunoprecipitation, ERK/Akt assays, cell proliferation/survival assay |
The Journal of biological chemistry |
Medium |
15010462
|
| 2006 |
GAB1 and SHP2 association is a critical event in liver regeneration: partial hepatectomy induces assembly of a Gab1-SHP2 complex in hepatocytes; liver-specific Gab1 knockout (LGKO) mice show defective ERK1/2 activation, decreased immediate-early gene expression, reduced cyclin levels, and suppressed hepatocyte proliferation after partial hepatectomy—phenocopying liver-specific Shp2 knockout mice. |
Liver-specific conditional Gab1 knockout, co-immunoprecipitation, ERK1/2 activation assay, gene expression analysis, BrdU proliferation assay |
Molecular and cellular biology |
High |
16738330
|
| 2006 |
GAB1 is required for VEGF-induced endothelial cell migration and capillary formation; GAB1 siRNA impairs PLCγ, ERK1/2, Src, and Akt activation by VEGF. GAB1 associates with VEGFR2, Grb2, PI3K, SHP2, Shc, and PLCγ in VEGF-stimulated cells; GAB1 mutants unable to bind SHP2 or PI3K mimic GAB1 depletion defects. |
siRNA knockdown, co-immunoprecipitation panel, overexpression of mutant GAB1, migration assay, tube formation assay, actin reorganization imaging |
The Journal of biological chemistry |
High |
17178724
|
| 2007 |
Knockin mouse analysis demonstrates distinct in vivo requirements: PI3K recruitment by GAB1 is essential for EGFR-mediated eyelid closure and keratinocyte migration, while GAB1-SHP2 interaction is essential for Met-directed placental development and muscle progenitor limb migration. Either direct (via Met-binding domain) or indirect (via Grb2) GAB1 recruitment to Met is sufficient for muscle precursor migration, but both modes are required for placenta, liver growth, and palate development. |
Knockin mice with point mutations in PI3K, SHP2, Grb2, and Met-binding sites of Gab1; developmental phenotypic analysis |
Proceedings of the National Academy of Sciences of the United States of America |
High |
17881575
|
| 2008 |
A new mechanism for Gab1 plasma membrane recruitment: ERK-dependent phosphorylation of Ser551 in Gab1 is required for its translocation to the plasma membrane; PI3K activity alone is insufficient. MAPK-dependent Ser551 phosphorylation represents a novel regulatory mode for PH domain function. |
ERK inhibitor, Ser551 phosphomutants, membrane fractionation/localization assay |
Journal of cell science |
Medium |
19050043
|
| 2009 |
Pak4 is a novel Gab1-binding partner: Gab1 and Pak4 associate after HGF stimulation and colocalize at lamellipodia; the interaction requires Gab1 phosphorylation but not Pak4 kinase activity; it is mediated by a unique Gab1 region (no homology to known interaction motifs) and the GEF-interacting domain of Pak4. Gab1/Pak4 synergize in epithelial dispersal, migration, and invasion; a Pak4-binding-defective Gab1 mutant fails to promote these responses. |
Co-immunoprecipitation, colocalization imaging, Pak4 siRNA knockdown, Gab1 mutant lacking Pak4-binding region, migration/invasion assays, morphogenesis assay |
Molecular and cellular biology |
Medium |
19289496
|
| 2009 |
Crk SH2 domain mediates Gab1 interaction and recruits Src to phosphorylate Gab1 at Y307; this requires Src specifically (not Yes/Fyn). Gab1-Y307F mutant fails to localize near the plasma membrane upon HGF stimulation and reduces cell migration, focal adhesion formation, and localization of Crk, FAK, and paxillin. |
Crk/SH2 mutants, Src/Yes/Fyn triple-knockout fibroblasts, PP2 Src inhibitor, Y307F Gab1 mutant, focal adhesion imaging, cell migration assay |
Cell research |
Medium |
19350053
|
| 2010 |
GAB1 scaffold is essential for dorsal ruffle formation downstream of Met, EGF, and PDGF receptors; GAB1 constitutively associates with N-WASP and recruits Nck into a dorsal-ruffle-localized complex upon RTK activation. Gab1ΔNck (Y407F) mutant fails to recruit Nck, prevents dorsal ruffles, decreases Met-dependent Rac activation, and impairs cell migration and epithelial remodeling. |
Gab1-null fibroblasts, co-immunoprecipitation (Gab1-N-WASP, Gab1-Nck), Gab1 Y407F mutant, dorsal ruffle quantification, Rac activation assay, migration assay |
Journal of cell science |
Medium |
20332103
|
| 2011 |
Endothelium-specific Gab1 knockout mice show impaired postnatal ischemic angiogenesis; HGF induces Gab1-SHP2 complex formation required for EC migration/proliferation via ERK1/2 and ERK5, and Gab1-p85 complex contributes to Akt activation and partial migration. HGF upregulates angiogenic genes (KLF2, Egr1) via Gab1-SHP2 complex. |
Endothelium-specific Gab1 KO mice, hindlimb ischemia model, co-immunoprecipitation, ERK1/2/5 assays, VEGF vs HGF gene transfer rescue, microarray |
Circulation research |
High |
21293003
|
| 2011 |
Endothelium-specific Gab1 KO mice have impaired VEGF-induced eNOS activation and angiogenesis; Gab1/SHP2 association is required for PKA activation and eNOS phosphorylation; active PKA rescues VEGF-induced eNOS activation in EGKO ECs. Gab1/SHP2 interaction is required for tube formation in vitro and ischemic angiogenesis in vivo. |
Endothelium-specific Gab1 KO mice, Matrigel plug assay, co-IP, active PKA rescue, eNOS activation assay, tube formation assay |
Proceedings of the National Academy of Sciences of the United States of America |
High |
21282639
|
| 2012 |
GAB1 acts as a PAR protein scaffold: GAB1 directly interacts with PAR1 and PAR3; GAB1 binding enhances PAR1 kinase activity; GAB1 brings PAR1 and PAR3 into a transient complex promoting PAR3 phosphorylation by PAR1. GAB1 and PAR6 compete for PAR3 PDZ1 binding. GAB1 depletion causes PAR3 hypophosphorylation, increased PAR3/PAR6 complex, and accelerated tight junction formation. GAB1 overexpression disrupts apical-basal polarity and promotes multilumen cyst formation in a PAR1/PAR3-dependent manner. |
Co-immunoprecipitation, PAR1 kinase assay, domain competition assay (GAB1 vs PAR6 for PAR3 PDZ1), siRNA knockdown, overexpression, transepithelial resistance assay, 3D cyst morphogenesis |
Molecular cell |
High |
22883624
|
| 2014 |
Gαi1/3 are required for KGF (FGF-7) activation of PI3K-AKT-mTORC1 through GAB1: upon KGF stimulation, Gαi1/3 form a complex with KGFR and are required for subsequent GAB1 recruitment, phosphorylation, and PI3K-p85 activation. Gαi1/3 shRNA knockdown inhibits KGF-induced cell proliferation, migration, and cyclin D1/fibronectin accumulation. |
Co-immunoprecipitation (Gαi1/3-KGFR-GAB1 complex), shRNA knockdown, PI3K/Akt/mTOR activity assays, cell proliferation and migration assays |
The Journal of investigative dermatology |
Medium |
25078664
|
| 2015 |
EGF promotes SHP2 binding to tyrosine-phosphorylated GAB1, activating SHP2, which augments TGFβ-induced EMT. Knockdown of SHP2 and reconstitution with phosphotyrosine-binding-impaired SHP2 eliminates EGF-mediated EMT augmentation, demonstrating that physical SHP2 recruitment to GAB1 (not just SHP2 catalytic activity per se) is required. |
siRNA knockdown + SHP2 mutant rescue, co-immunoprecipitation, E-cadherin/vimentin expression, cell scatter assay |
Journal of cell science |
Medium |
26359300
|
| 2015 |
EGFR-activated Src family kinases (SFKs) maintain GAB1 phosphorylation and GAB1-SHP2 complexes at a cytosolic site distal from EGFR; a delay in SFK inactivation after EGFR inactivation prolongs GAB1-SHP2 complex persistence beyond EGFR phosphorylation. This SFK-dependent mechanism is specific to EGFR and does not occur downstream of c-MET. |
Quantitative co-immunoprecipitation time-course, SFK inhibitors, computational modeling validated by experiment, EGFR vs c-MET comparison |
Science signaling |
Medium |
25969544
|
| 2015 |
Gab1 is required for normal hair cycle and hair follicle stem cell (HFSC) quiescence: conditional Gab1 knockout (K14-Cre or Krox20-Cre) prevents catagen entry; HFSCs lose quiescence and become exhausted. Conditional expression of gain-of-function Mek1(DD) (by Krox20-Cre) rescues hair cycle deficits and restores HFSC quiescence, placing GAB1 upstream of Shp2 and MAPK in this pathway. |
Conditional Gab1 knockout mice, Mek1(DD) gain-of-function knockin rescue, HFSC quantification, hair cycle analysis |
Cell reports |
High |
26456821
|
| 2016 |
The non-receptor tyrosine kinase FER phosphorylates Met at Tyr1349 in an HGF-independent and Met autophosphorylation-independent manner; this promotes GAB1 recruitment and phosphorylation and activates the SHP2-ERK signaling pathway specifically (without activating Akt), thereby promoting ovarian cancer cell motility, invasion, and metastasis. |
FER siRNA/shRNA, phosphosite-specific antibodies, co-immunoprecipitation, kinase assay, cell migration/invasion, in vivo metastasis model |
Genes & development |
High |
27401557
|
| 2018 |
A p.Gly116Glu substitution in the GAB1 PH domain causes DFNB26 recessive profound deafness. METTL13 (dominant modifier DFNM1; p.Arg544Gln) coimmunoprecipitates with GAB1 and SPRY2, forming at least a tripartite complex; METTL13 modifier allele rescues GAB1 morphant phenotype in zebrafish. GAB1 p.Gly116Glu mutation dysregulates HGF, MET, SHP2, and SPRY2 expression; SPRY2 dysregulation is corrected in the presence of the METTL13 suppressor. |
Co-immunoprecipitation (METTL13-GAB1-SPRY2 complex), zebrafish morpholino rescue with human mRNA, gene expression profiling in human lymphoblastoid cells, human genetic mapping |
The Journal of clinical investigation |
High |
29408807
|
| 2020 |
GAB1 is an essential effector of PDGF signaling in oligodendrocyte precursor cells (OPCs): conditional Gab1 deletion causes CNS hypomyelination by impairing OPC differentiation. GAB1 binds downstream to GSK3β and regulates its activity, thereby affecting β-catenin nuclear accumulation and expression of myelination-related transcription factors. |
Conditional Gab1 knockout in oligodendrocyte lineage, GSK3β binding (co-immunoprecipitation), β-catenin localization, transcription factor expression analysis, myelin staining |
eLife |
High |
31944179
|