11q14.1

Breast cancer

GAB2 is frequently over-expressed in human breast cancer cell lines and primary tumours. Overexpression of GAB2 has been shown to be an early event in breast cancer development. In response to EGF, insulin and bFGF stimulation, GAB2 becomes tyrosine phosphorylated indicating that these RTKs, which are implicated in breast cancer development or progression, use this docking protein to amplify their signals. There might be several, not necessarily mutually exclusive mechanisms by which GAB2 is up-regulated in breast cancer such as the amplification of the GAB2 locus, which resides in a region commonly amplified in breast cancers or the aberrant activity of the E2F transcription factor, which is often dysregulated in tumours and binds directly to the human GAB2 promoter. Furthermore, the expression of both GAB2 mRNA and protein is induced by estradiol in an estrogen receptor-dependent manner. Modelling GAB2 expression levels to those observed in breast cancer in the immortalised, but non-transformed, human mammary epithelial cell MCF-10A implies that overexpression of this docking protein contributes to various aspects of malignant transformation such as increased proliferation and reduced growth factor requirements.
Studies from various laboratories using the MCF-10A model system as well as transgenic mouse models suggest that GAB2 also cooperates with other oncogenes implicated in breast cancer development such as HER2 and SRC. Indeed, a recent study by Bocanegra et al. (2009) has shown that small interfering RNA (siRNA)-mediated knockdown of GAB2 in breast cancer lines with GAB2 amplification revealed a dependency on GAB2 for cell proliferation, cell-cycle progression, survival and invasion, likely mediated through altered phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signaling. These findings are in agreement with studies in MCF-10A cells in which ectopically expressed GAB2 affects these biological parameters via the same effector pathways. GAB2 knockdown also impaired the proliferation and survival in the BT474 cell line, which contains a ERBB2 amplification, consistent with previous studies implicating GAB2 as an important downstream effector of this receptor tyrosine kinase.

Melanoma

Two recent studies implicate GAB2 in malignant melanoma. Firstly, Horst et al. (2009) have shown that the GAB2 gene is amplified and/or over-expressed in 11% and 50% of human metastatic melanomas, respectively. Moreover, Chernoff et al. (2009) demonstrated that GAB2 amplification is associated with melanoma arising from sun-protected sites and often occurs independently from oncogenic NRAS or BRAF mutations or amplification of the KIT gene. Importantly, knockdown and over-expression experiments revealed that GAB2 enhances the migratory and invasive behaviour of melanoma cells. In contrast to metastatic melanoma, normal human melanocyte lines, melanocytic nevi and primary melanomas displayed low GAB2 expression levels suggesting that GAB2 overexpression might represent a marker of neoplastic progression.

Myeloid leukemias

The first evidence for a critical contribution of GAB2 to leukemogenesis was the observation that myeloid progenitors from GAB2-deficient mice are resistant to transformation by the BCR-ABL oncoprotein, which arises from a chromosomal translocation found in more than 90% of patients with chronic myeloid leukaemia (CML). Phosphorylation of Y177 within the BCR moiety leads to recruitment of the GRB2/GAB2 complex and downstream signalling via SHP2 and PI3K, two crucial events for enhanced proliferation and survival. Similarly, the oncogenic BCR-FGFR1 fusion protein, which consists of a BCR-derived moiety and the tyrosine kinase domain of the fibroblast growth factor receptor 1 (FGFR1), drives the tyrosine phosphorylation of GAB2 in murine bone marrow cells and their malignant transformation through phospho-Y177 mediated GRB2 association.
These findings suggest that GRB2-mediated recruitment of GAB2 to oncogenic fusion protein tyrosine kinases is a critical event for the induction of a CML-like disease.
The contribution of GAB2 to BCR-ABL signaling is further supported by the observation that shRNA-mediated silencing of endogenous GAB2 inhibits proliferation and colony formation of CD34+ cells from CML patients.
GAB2 is also involved in the pathogenesis of several other leukemias. The oncogenic fusion kinases TEL-ABL and TEL-JAK2 engage GAB2 in a similar manner as BCR-ABL.
The gene encoding the GAB2 interaction partner SHP2, represents the most common target of somatic mutations in juvenile myelomonocytic leukemia (JMML), a rare, albeit aggressive myelo-proliferative disorder occurring in children. The most frequently JMML-associated mutation, E76K, confers enhanced catalytic activity to SHP2 and requires GAB2 for transformation of primary murine myeloid progenitors.

Other neoplasia

Amplification and/or over-expression of the human GAB2 gene has been also recently reported for ovarian and gastric carcinoma as well as for acute myeloid leukemia (AML). However, additional functional studies are needed to dissect the role that GAB2 plays in these malignancies.