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Gab2

Official Full Name
GRB2-associated binding protein 2
Background
The Grb-associated binder (Gab) family is a family of adaptor proteins recruited by a wide variety of receptor tyrosine kinases (RTKs) such as EGFR, HGFR, insulin receptor, cytokine receptor and B cell antigen receptors. Upon stimulation of RTKs by their
Synonyms
GAB2; GRB2-associated binding protein 2; GRB2-associated-binding protein 2; Grb2 associated binder 2; KIAA0571; pp100; Grb2-associated binder 2; growth factor receptor bound protein 2-associated protein 2

Grb2-associated binding protein 2 (GAB2) is a scaffolding protein which contains diverse structural domains and docking sites that serve as a platform for the assembly of signaling systems. GAB2 is expressed ubiquitously, but it is most highly expressed in heart, brain, kidney, lung, testis, and ovary. Although GAB2 itself lacks enzymatic activity, it works downstream of receptor tyrosine kinases (RTK) and non-RTKs, such as cytokine, to transmit and amplify signals to downstream effectors. After stimulation, GAB2 becomes phosphorylated on critical tyrosine residues creating binding sites for diverse targets involved in signal transduction. Therefore, GAB2 acts as a mediator of essential cellular processes including proliferation, survival, differentiation, and migration.

Structure and function of Gab2

Gab2 is composed of a central praline‑rich domain (PRD), an N‑terminal Pleckstrin homology (PH) domain and multiple tyrosines within potential binding motifs, which are favored by diverse SH‑2 and 3 domain‑containing proteins. All three domains, especially the PH domain, are highly conserved in the process of organic evolution.

The N‑terminal PH domain’s binding to PIP3 is involved in membrane recruitment of Gab2. Prior reports have indicated that the PH domain could also be involved in regulating intracellular signaling (Fas‑signaling pathway), not just a localization module. The PRD contains numerous PXXP motifs, which mediate the interaction with SH3 domain‑containing proteins, including Grb2. There are various sites of tyrosine phosphorylation, which may interact with SH2 domain‑containing proteins, including p85 and SHP2. This interaction is significant for the function of Gab2 in mediating intracellular signaling pathways, which are important for normal cell growth, development, differentiation and apoptosis (Figure 1).

GAB2 Figure 1. Schematic diagram of GAB2 signaling and GAB2 protein structure (Adams S J, et al., Molecular Cancer Research).

Gab2 and cancer

The DNA amplification is a common mechanism resulting in oncogenic activation in human cancer. GAB2 is located on chromosomal band 11q14.1. Amplification of 11q13-14.1 is often observed in human malignancies. The identification of GAB2 as a potential oncogene comes from studies in breast cancer, melanoma, leukemia, and ovarian cancer.

  • Breast cancer

It was reported that the expression of Gab2 is reduced in invasive cancer and lymph node metastases, compared with ductal carcinoma in situ (DCIS), although it remains higher than in normal breast tissue. Overexpression of Gab2 in MCF‑10A cells, an immortalized and non‑transformed human mammary epithelial cell line, contributes to increased proliferation and alterations in dependency on EGF and other growth factors. By comparison, ablation of Gab2 in several breast cancer cell lines, inhibiting genomic amplifications, results in a decrease in proliferation, because of a reduction in cell‑cycle progression and increased apoptosis, and a reduction in their invasive potential. Overexpression of Gab2 in MCF‑10A cells promotes enhanced cell migration by modulating the activation of Ras homolog gene family, member A, which is dependent on the SHP2‑binding sites. Gab2 is required for efficient ErbB2‑driven mammary tumorigenesis and metastatic spread. Gab2 acts downstream of Neu, also termed HER2 and ErbB2, and is tyrosyl‑phosphorylated upon activation of signal transduction.

  • Melanoma

The development of melanoma is closely linked to oncogenic activation of ERK and PI3-K-AKT signaling. GAB2 scaffolding protein is crucial to the propagation of these signaling cascades and has been implicated as a driver of melanomagenesis. GAB2 is expressed at significantly higher levels in metastatic melanomas as compared with primary melanomas and melanocytic nevi, and thus can be seen as a marker of neoplastic progression. Silencing of GAB2 in metastatic melanoma cell lines results in a decrease in their invasive potential, whereas overexpression in primary melanomas promotes migration and invasion. Furthermore, in vivo studies show that overexpression of GAB2 results in enhanced tumor growth and development of metastases.

  • Leukemia

The first evidence for the pivotal contribution of Gab2 to leukemogenesis was an investigation, which indicated that myeloid progenitors from Gab2‑deficient mice are resistant to transformation by the BCR‑ABL oncoprotein. And the oncoprotein arises from a chromosomal translocation found in >90% of patients with chronic myeloid leukaemia (CML). The oncogenic protein tyrosine kinase, BCR‑ABL, interacts with Grb2 and Gab2 signaling, and triggers hematopoietic cell proliferation. In BCR/ABL‑positive CML bone marrow, Gab2‑positive myeloid cells are significantly more frequent, compared with normal bone marrow. These findings demonstrate that Gab2 is part of a protein complex that is important, if not essential, in BCR/ABL‑driven CML. Moreover, BCR‑ABL1 is not only present in CML patients, but also occurs in 20‑30% of patients with acute lymphoblastic leukemia (ALL). Therefore, these studies suggest that human CML could depend on BCR/ABL‑driven Gab2 signaling and identify Gab2 as a potential therapeutic target.

  • Ovarian cancer

Genomic amplifications of Gab2 have been described in around 16% of ovarian carcinoma cases. The expression of Gab2 predominantly regulates the migratory behaviors of ovarian cancer cells, and overexpression of Gab2 enhances invasion and migration, and downregulates the expression of E‑cadherin in ovarian cancer cells with low baseline expression levels of Gab2. On the contrary, silencing of Gab2 inhibits the migration and invasion, and positively regulates E‑cadherin expression in ovarian cancer cells with high‑Gab2 expression. Moreover, Dunn GP et al identified that Gab2 as an ovarian cancer oncogene, which potently transforms immortalized ovarian and fallopian tube secretory epithelial cells via the activation of PI3K signaling. The novel Gab2/PI3K/Zeb1 pathway can be targeted by PI3K and mammalian target of rapamycin (mTOR) inhibitors and can be potentially used to treat Gab2‑driven ovarian cancer combined with standard chemotherapy.

References:

  1. Osinalde N, et al. Changes in Gab2 phosphorylation and interaction partners in response to interleukin (IL)-2 stimulation in T-lymphocytes. Sci Rep, 2016, 6:23530.
  2. Adams S J, et al. GAB2 - A Scaffolding Protein in Cancer. Molecular Cancer Research, 2012, 10(10):1265-1270.
  3. Dunn G P, et al. In vivo multiplexed interrogation of amplified genes identifies GAB2 as an ovarian cancer oncogene. Proc Natl Acad Sci U S A, 2014, 111(3):1102-1107.
  4. Ding C B, et al. Structure and function of Gab2 and its role in cancer (Review). Molecular Medicine Reports, 2015, 12(3):4007-4014.
  5. Zhang X, et al. Gab2 Phosphorylation by RSK Inhibits Shp2 Recruitment and Cell Motility. Molecular & Cellular Biology, 2013, 33(8):1657-1670.
  6. Ding J, et al. Inhibition of PI3K/mTOR overcomes nilotinib resistance in BCR-ABL1 positive leukemia cells through translational down-regulation of MDM2. Plos One, 2013, 8(12):e83510.

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