Disease relevance of Gab1

• Adaptor molecule Crk is required for sustained phosphorylation of Grb2-associated binder 1 and hepatocyte growth factor-induced cell motility of human synovial sarcoma cell lines [1].
• To analyze in vitro the mechanistic implications of beta1A, beta1C, and Gab1 deregulation in prostate cancer, we investigated whether expression of either beta1 variant in beta1-null cells affected IGF-IR localization [2].

High impact information on Gab1

• Deletion of Gab1 in the liver leads to enhanced glucose tolerance and improved hepatic insulin action [3].
• Mice lacking Gab1 die during embryogenesis and show defective responses to several stimuli [4].
• Here we show that Gab1 interacts directly with the c-met-encoded receptor tyrosine kinase but not with a number of other tyrosine kinases from different subfamilies [5].
• Thus we have discovered a new phosphotyrosine interaction domain in Gab1 and shown that Gab1 is the substrate of the c-Met receptor tyrosine kinase that mediates epithelial morphogenesis [5].
• Gab1 encodes an adaptor protein that transduces signals elicited by tyrosine kinase receptors, for instance the c-Met receptor, and plays a role in the migration of muscle progenitor cells [6].

Biological context of Gab1

• Gab1 is a scaffolding/docking protein that has been suggested to play a role in signal transduction downstream of certain plasma membrane receptors, including platelet-derived growth factor (PDGF) receptors [7].
• Gab1 acts to diversify the signal downstream from the Met receptor tyrosine kinase through the recruitment of multiple signaling proteins, and is essential for epithelial morphogenesis [8].
• Gab1 contributes to cytoskeletal reorganization and chemotaxis in response to platelet-derived growth factor [7].
• The latter requires a novel amino acid sequence present in the Met-binding domain of Gab1 but not Gab2 [8].
• We demonstrate that, albeit no association is detected between the Tpo receptor mpl and Gab proteins, Y112 located in the C-terminal cytoplasmic domain of mpl is required for Gab1/2 tyrosine phosphorylation [9].

Anatomical context of Gab1

• In this report, we explore the role of Gab1 in FGF1 signaling by using mouse embryo fibroblasts (MEFs) derived from Gab1(-/-) or FRS2alpha(-/-) mice [10].
• To further study the role of Gab1 in PDGF signaling, we transfected porcine aortic endothelial cells with a doxycycline-inducible Gab1 construct [7].
• Gab1 expression also enhanced the formation of lamellipodia and cellular protrusions [7].
• Conversely, Gab family members Gab1, Gab2, and Gab3 may play specific roles in different leukocytes [11].
• CXCR4 and Gab1 cooperate to control the development of migrating muscle progenitor cells [6].

Associations of Gab1 with chemical compounds

• Development of an efficient "substrate-trapping" mutant of Src homology phosphotyrosine phosphatase 2 and identification of the epidermal growth factor receptor, Gab1, and three other proteins as target substrates [12].
• ET-1-induced Gab1 tyrosine phosphorylation was also inhibited by LY294002, which inhibits phosphoinositide 3-kinase (PI 3-kinase) enzymes [13].
• Our results show that Gab1 is phosphorylated in a dose- and time-dependent manner after H(2)O(2) triggering [14].
• Role of Gab1 in UV-induced c-Jun NH2-terminal kinase activation and cell apoptosis [15].
• Additionally, we have found that the newly identified insulin receptor substrate Gab-1 (Grb2-associated binder-1) is tyrosine-phosphorylated following sorbitol stimulation [16].
• Recruitment of phosphatidylinositol 3-kinase by Gab1 is essential for EGF receptor-mediated embryonic eyelid closure and keratinocyte migration, and the Gab1-Shp2 interaction is crucial for Met receptor-directed placental development and muscle progenitor cell migration to the limbs [17].

Physical interactions of Gab1

• Gab1 was constitutively complexed with JNK and became tyrosine phosphorylated in UV-irradiated cells [15].

Enzymatic interactions of Gab1

• Partial hepatectomy (PH) rapidly and transiently induced assembly of a complex comprising Shp2 and tyrosine-phosphorylated Gab1 in wild-type hepatocytes [18].

Regulatory relationships of Gab1

• Furthermore, phosphorylated Gab-1 binds and activates phosphatidylinositol 3-kinase (PI3K) in response to osmotic shock [16].
• An anti-E-cadherin antibody decreased cell-cell adhesion-dependent tyrosine phosphorylation of Gab-1, whereas the expression of E-cadherin specifically induced tyrosine phosphorylation of Gab-1 [19].
• We propose that the loss of adhesion dependent signals required for cell cycle progression is compensated through Met induced Gab1/Crk signals [20].
• Gab-1 is capable of regulating these biological end points despite the absence of IGF-1 stimulated tyrosine phosphorylation [21].

Other interactions of Gab1

• The scaffolding proteins Gab1 and/or Gab2 were candidates for this role [22].
• We found that CXCR4 and Gab1 interact genetically [6].
• Furthermore, we showed that the negative role of Gab1 required its Src homology 2-containing tyrosine phosphatase-2 binding sites [23].
• In isolated murine carotid arteries, flow-induced vasodilatation was prevented by a PKA inhibitor as well as by overexpression of either the YF-Gab1 or the dominant-negative SHP2 mutant [24].
• RESULTS: We used fibroblasts isolated from Gab1-/- mouse embryos to explore the mechanism of EGF stimulation of the PI-3 kinase/Akt anti-apoptotic cell signaling pathway [25].

Analytical, diagnostic and therapeutic context of Gab1

• To reveal the functions of Gab1 in vivo, we generated mice lacking Gab1 by gene targeting [26].

References