GAB2

GRB2-associated-binding protein 2 also known as GAB2 is a protein that in humans is encoded by the GAB2 gene. GAB2 is a docking protein with a conserved, folded PH domain attached to the membrane and a large disordered region, which hosts interactions with signaling molecules. It is a member of the GAB/DOS family localized on the internal membrane of the cell. It mediates the interaction between receptor tyrosine kinases (RTKs) and non-RTK receptors serving as the gateway into the cell for activation of SHP2, Phosphatidylinositol 3-kinase (PI3K), Grb2, ERK, and AKT and acting as one of the first steps in these signaling pathways. GAB2 has been shown to be important in physiological functions such as growth in bone marrow and cardiac function. GAB2 has also been associated with many diseases including leukemia and Alzheimer's disease.

Discovery

GAB proteins were one of the first docking proteins identified in the mammalian signal transduction pathway. GAB2 along with many other adaptor, scaffold, and docking proteins, was discovered in the mid-1990s during the isolation and cloning of protein tyrosine kinase substrates and association partners. GAB2 was initially discovered as a binding protein and substrate of protein tyrosine phosphatase Shp2/PTPN11. Two other groups later cloned GAB2 by searching DNA database for protein with sequence homology to GAB1.

AKT1

Through the PI3K signaling pathway, PI3K activates the serine/threonine protein kinase (AKT), which in turn through phosphorylation inactivates GSK3. This in turn causes the phosphorylation of tau and amyloid production.

CRKL

CT10 regulator of kinase (Crk) is also known as the breast cancer anti-oestrogen resistance protein. It plays a role in both fibroblast formation and breast cancer. The YXXP binding motif is required for the association of CRKL and GAB2. This leads to the activation of c-Jun N-terminal kinase(JNK) as part of the JNK signaling pathway.

Grb2

Upon stimulation by growth hormone, insulin, epidermal growth factor (EFG), etc., the GAB2 protein can be recruited from the cytoplasm to the cell membrane, where it forms a complex with Grb2 and SHC. The interaction between GAB2 and Grb2 requires a PX3RX2KP motif in order to produce a regulatory signal. The activated GAB2 can now recruit SH2 domain-containing molecules, such as SHP2 or PI3K to activate signaling pathways.

PI3K

The p85 subunit of PI3K (or PIK3) possessed the SH2 domain required to be activated by GAB2. The activation of the PI3K signaling pathway produces increased amyloid production and microglia-mediated inflammation. The immunoglobulin receptor FceRI requires GAB2 as a necessity for mast cells to activate PI3K receptor to create an allergic response. In a study of knockout mice lacking the GAB2 gene, subjects experienced impaired allergic reactions, including passive cutaneous and systemic anaphylaxis. PI3K is found to be mutated in most breast cancer subtypes. Sufficient GAB2 expression by these cancerous subtypes proves necessary in order to sustain a cancerous phenotype.

PLCG2

The erythropoietin hormone (Epo) is responsible for the regulation and proliferation of erythrocytes. Epo is able to self phosphorylate, which causes recruitment of SH2 proteins. An activated complex of GAB2, SHC, and SHP2 is required for binding of Phospholipase C gamma 2 (PLCG2) through its SH2 domain, which activates PIP3.

PTPN11

Protein tyrosine phosphatase non-receptor 11 (PTPN11) interaction with GAB2 is part of the Ras pathway. Mutations found in PTPN11 cause disruption in the binding to GAB2, which in turn impairs correct cellular growth. Thirty-five percent of patients diagnosed with JMML show activating mutations in PTPN11.

RICS

GC-GAP is part of the Rho GTP-ase activating protein family (RICS). It contains a highly proline-rich motifs that allow favorable interactions with GAB2. GC-GAP is responsible for the proliferation of astroglioma cells.

SHC1

The interaction between GAB2 and Grb2 at the cell membrane recruits another adaptor protein, the Src homology domain-containing transforming protein 1 (SHC1), before being able to recruit SH2 domain-containing molecules.

Clinical Implications

Alzheimer's disease

Ten SNPs of GAB2 have been associated with late-onset Alzheimer's disease (LOAD). However, this association is found only in APOE ε4 carriers. In LOAD brains, GAB2 is overexpressed in neurons, tangle-bearing neurons, and dystrophic neuritis. GAB2 has been indicated in playing a role in the pathogenesis of Alzheimer's disease via its interaction with tau and amyloid precursor proteins. GAB2 may prevent neuronal tangle formation characteristic of LOAD by reducing phosphorylation of tau protein via the activation of the PI3K signaling pathway, which activates Akt. Akt inactivates Gsk3, which is responsible for tau phosphorylation. Mutations in GAB2 could affect Gsk3-dependent phosphorylation of tau and the formation of neurofibrillary tangles. Interactions between GAB2-Grb2 and APP are enhanced in AD brains, suggesting an involvement of this coupling in the neuropathogenesis of AD.

Cancer

GAB2 has been linked to the oncogenesis of many cancers including colon, gastric, breast, and ovarian cancer. Studies suggest that GAB2 is used to amplify the signal of many RTKs implicated in breast cancer development and progression. GAB2 has been particularly characterized for its role in leukemia. In chronic myelogenous leukemia (CML), GAB2 interacts with the Bcr-Abl complex and is instrumental in maintaining the oncogenic properties of the complex. The Grb2/GAB2 complex is recruited to phosphorylated Y177 of the Bcr-Abl complex leading to Bcr-Abl-mediated transformation and leukemogenesis. GAB2 also plays a role in juvenile myelomonocytic leukemia (JMML). Studies have shown the protein's involvement in the disease via the Ras pathway. In addition, GAB2 appears to play an important role in PTPN11 mutations associated with JMML.

Text derived from https://en.wikipedia.org/w/index.php?oldid=1366292223 under CC BY-SA 4.0; modifications have been made.

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