GAB1

Official Full Name

GRB2 associated binding protein 1

Organism

Homo sapiens

GeneID

2549

Background

The protein encoded by this gene is a member of the IRS1-like multisubstrate docking protein family. It is an important mediator of branching tubulogenesis and plays a central role in cellular growth response, transformation and apoptosis. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2008]

Synonyms

DFNB26;

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Detailed Information

Grb2-associated binder 1 (Gab1) is a member of the Gab/Daughter-of-sevenless family of docking proteins, which in mammals also includes Gab2 and Gab3. Gab1 couples to a variety of receptor and non-receptor tyrosine kinases, including the epidermal growth factor receptor (EGFR), Src and c-Met, and elicits a variety of biological responses, including proliferation, migration and branching tubulogenesis. It contains an N-terminal pleckstrin homology (PH) domain, a central region that harbors direct interaction sites for Grb2 and c-Met, and many tyrosine phosphorylation sites. Recruitment of Gab1 to c-Met occurs via direct binding, and also via an indirect mechanism involving a Grb2 ‘bridge’. The latter mechanism is the only recruitment mode for other receptors such as the EGFR. The Gab1 PH domain binds phosphatidylinositol 3, 4, 5 trisphosphate, and this interaction localizes Gab1 to the plasma membrane in the vicinity of activated growth factor receptors and also to cell-cell contacts.

Effector proteins involved in Gab1-mediated signal transduction

Gab1 is tyrosine-phosphorylated in response to a number of growth factors (including vascular endothelial growth factor (VEGF), nerve growth factor (NGF), platelet-derived growth factor (PDGF), hepatocyte growth factor (HGF), and epidermal growth factor (EGF)) and other stimuli, thereby propagating signals which are essential for cell proliferation, motility, and erythroblast development. However, hyper-phosphorylation in serine and threonine of Gab1 (by PKC-α and PKC-β1) has been shown to negatively regulate HGF-induced biological responses that are important for Gab1-induced signaling required for angiogenesis.

Gab1 is essential for embryo survival, because Gab1^−/− mice are not viable and only reach days 14 to 18 of gestation. Further analysis indicates that these mice have multiple developmental defects in the heart, liver, spleen, placenta and muscle development. The phenotype of Gab1deficient mice showed similarity with those deficient of c-Met, HGF, PDGF, and EGF signaling pathways. Sun et al. reported that cardiomyocyte-specific Gab1 knockout mice exhibited an increase in infarct size and a decrease in cardiac function after ischemia/reperfusion (I/R) injury, suggesting that Gab1 is also essential for cardioprotection against I/R oxidative injury. Additionally, it has been reported that Gab1 and Gab2 may have the redundant roles for maintenance of cardiac function via neuregulin-1/ErbB signaling when using cardiomyocyte-specific Gab1/Gab2 double knockout mice.

Gab1 and angiogenesis

It has reported the vital role of Gab1 in regulating postnatal angiogenesis using endothelial cell-specific Gab1 knockout (Gab1-ecKO) mice and hindlimb ischemia models. These studies showed that Gab1-ecKO mice have severe defects in angiogenesis after hindlimb ischemia. Impaired blood flow recovery, low capillary density and necrotic limb were observed 2 weeks after the femoral artery ligation in Gab1-ecKO mice, while the WT control mice showed a time-dependent recovery of blood flow and increased capillary density in the gastrocnemius muscle.

In addition to hindlimb ischemia-induced angiogenesis, Gab1 was also shown to be crucial for the tumor angiogenesis. Zhao et al. demonstrated a significantly low level of capillary density in tumors engrafted in the Gab1-ecKO mice as well as dramatically decreased tumor weight and volume. Taken together, Gab1 functions, as a key molecule that regulates both VEGF- and HGF-mediated downstream signaling pathways, are involved in EC stabilization, proliferation, migration and survival which are crucial for angiogenic processes (Figure 1).

Gab1 Figure 1. Schematic representation of the role of Gab1 in growth factor signaling and angiogenesis.

Gab1 and disease

The GAB2 gene is amplified and/or overexpressed in gastric, breast and ovarian cancer, as well as in metastatic melanoma and acute myeloid leukemia. In one study, transcript profiling detected increased Gab1 expression in Bcr-Abl-positive versus negative adult acute lymphoblastic leukemia, whereas, in a second study, Gab1 expression was associated with a particular subtype of medulloblastoma. Moreover, a screen for somatic mutations in breast and colorectal cancers identified two mutations in Gab1. The first, Y83C, was detected in a primary ductal breast cancer, while the second, T387N, occurred in the breast cancer cell line HCC1954.

Urothelial carcinoma is the most common type of malignancy in long-term dialysis patients and kidney transplant recipients. The mTORCs pathway is important in urothelial carcinoma and it is already known that EGF triggers mTORCs activation. A high percentage of EGFR-positive cases were observed in high-grade urothelial carcinoma. These data suggest that EGFR plays a crucial role in urothelial carcinoma and Gab1 is a major downstream protein in EGFR signal transduction pathway. Thus, Gab1 may play a crucial role in regulating EGF-mediated mTORC activity in urothelial carcinoma. Not only urothelial carcinoma, it has been reported that mTORCs are activated in many different carcinomas, such as melanoma, renal cell carcinoma and prostate tumors. mTORC1 promotes HIF-1α and VEGF protein and mRNA expression to induce angiogenesis in renal cell carcinoma. Through the activation of AKT and SGK, mTORC2 may directly drive tumorigenesis.

References:

Shioyama W, et al. Docking protein Gab1 is an essential component of postnatal angiogenesis after ischemia via HGF/c-met signaling. Circulation Research, 2011, 108(6):664-75.
Wang W, et al. Essential roles of Gab1 tyrosine phosphorylation in growth factor-mediated signaling and angiogenesis. International Journal of Cardiology, 2015, 181:180-184.
Ortizpadilla C, et al. Functional characterization of cancer-associated Gab1 mutations. Oncogene, 2013, 32(21):2696-2702.
Chang C H, et al. Gab1 is essential for membrane translocation, activity and integrity of mTORCs after EGF stimulation in urothelial cell carcinoma. Oncotarget, 2015, 6(3):1478-89.
Chen L, et al. Novel inhibitors induce large conformational changes of GAB1 pleckstrin homology domain and kill breast cancer cells. Plos Computational Biology, 2015, 11(1):e1004021.
Yang Z, et al. The signaling adaptor GAB1 regulates cell polarity by acting as a PAR protein scaffold. Molecular Cell, 2012, 47(3):469-483.

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