GAB2--a scaffolding protein in cancer

Abstract

Adaptor or scaffolding proteins mediate protein-protein interactions that drive the formation of protein complexes. Grb2-associated binding protein 2 (GAB2) scaffolding protein is an intermediary molecule that links plasma membrane receptor signaling including receptor tyrosine kinases with the downstream effectors, such as protein tyrosine phosphatase, nonreceptor type 11 (SHP2), p85 subunit of phosphoinositide-3 kinase (PI3-K), phospholipase C-gamma 1 (PLC-γ), v-crk sarcoma virus CT10 (CRK), Src homology 2 domain containing transforming protein 1 (SHC), and SH2 containing inositol phosphatase (SHIP). Although, well described in signal transduction, its role in cancer has recently been emerging especially in leukemia, breast and ovarian cancer, and melanoma. GAB2 is essential for two major signal transduction pathways in cancer, the PI3-K-AKT and extracellular signal-regulated kinase (ERK) signaling pathways, and thus regulates a number of key cellular processes. This review focuses on structure and function of GAB2, its regulatory proteins, emerging role in cancer, and potential as a therapeutic target.

Figure 1

Schematic diagram of GAB2 signaling and the GAB2 protein structure. The two main effector arms of GAB2 signaling, SHP2-ERK and PI3K-AKT, are shown. Structural domains of the GAB2 protein including an N-terminal PH domain critical for membrane localization and central proline-rich regions mediating interactions with SH2- and SH3-domain containing proteins are indicated. Interacting partners of GAB2 such as GRB2, p85, SHP2, CRK, PLCγ, and 14-3-3 are shown.