Function, regulation and pathological roles of the Gab/DOS docking proteins

Abstract

Since their discovery a little more than a decade ago, the docking proteins of the Gab/DOS family have emerged as important signalling elements in metazoans. Gab/DOS proteins integrate and amplify signals from a wide variety of sources including growth factor, cytokine and antigen receptors as well as cell adhesion molecules. They also contribute to signal diversification by channelling the information from activated receptors into signalling pathways with distinct biological functions. Recent approaches in protein biochemistry and systems biology have revealed that Gab proteins are subject to complex regulation by feed-forward and feedback phosphorylation events as well as protein-protein interactions. Thus, Gab/DOS docking proteins are at the centre of entire signalling subsystems and fulfil an important if not essential role in many physiological processes. Furthermore, aberrant signalling by Gab proteins has been increasingly linked to human diseases from various forms of neoplasia to Alzheimer's disease.In this review, we provide a detailed overview of the structure, effector functions, regulation and evolution of the Gab/DOS family. We also summarize recent findings implicating Gab proteins, in particular the Gab2 isoform, in leukaemia, solid tumours and other human diseases.

Anti-apoptotic Role of Caspase-cleaved GAB1 Adaptor Protein in Hepatocyte Growth Factor/Scatter Factor-MET Receptor Protein Signaling

“…Overexpression of p35-GAB1, itself activated by HGF/SF, was capable of causing the subsequent downstream activation of the PI3K-AKT pathway as well as cell migration and resistance to apoptotic stress. On the other hand, p35-GAB1, in agreement with the loss of the C-terminal part of GAB1, was not capable to recruit SHP2 any more, and its overexpression in cells was associated with a reduced activation of the RAS-ERK pathway, as expected for the role of SHP2 in GAB1 signaling (7,8,14,15). Taken together, these data indicate that the caspase cleavage of the GAB1 docking adaptor protein can maintain HGF/SF-induced cell survival/resistance to apoptosis (Fig.…”

“…It contains the GAB1-MBD and has conserved one of the two GRB2 binding motifs (aa 516 -525) and all three SH2 binding sites for p85-PI3K but has lost the C-terminal SHP2-interacting domains containing crucial Tyr phosphorylation sites (Tyr-627 and -659) (7,8,14,15) (Fig. 8b).…”

Enhanced GAB2 Expression Is Associated with Improved Survival in High-Grade Serous Ovarian Cancer and Sensitivity to PI3K Inhibition

“…Consistent with the increase in copy number gain at 8q observed in GAB2 overexpressing tumors, the protein with the most significant association with GAB2 overexpression was c-Myc (P ¼ 3.9 Â 10 À5 , ANOVA of RPPA data using GAB2 high-versus low-expressing tumors as defined above). Previous studies have suggested that GAB2 functions as a scaffold to facilitate activation of pathways downstream of a receptor tyrosine kinase, such as the PI3K pathway (21). We assessed whether elevated GAB2 expression correlated with downstream activation of the PI3K pathway by TCGA RPPA protein levels of pAKT-473, pAKT-308, and pPRAS40-246.…”

Acquired Substrate Preference for GAB1 Protein Bestows Transforming Activity to ERBB2 Kinase Lung Cancer Mutants

“…Therefore, GAB1-targeted anti-cancer therapies could be more efficacious by blocking oncogenic signaling mediated by individual receptor kinases and their crosstalk. Strategies to target GAB1 and other docking proteins have been proposed (15,37).…”