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Review
. 2015 Feb 15:181:180-4.
doi: 10.1016/j.ijcard.2014.10.148. Epub 2014 Oct 24.

Essential roles of Gab1 tyrosine phosphorylation in growth factor-mediated signaling and angiogenesis

Weiye Wang  1 , Suowen Xu  1 , Meimei Yin  1 , Zheng Gen Jin  2
Affiliations
Review

Essential roles of Gab1 tyrosine phosphorylation in growth factor-mediated signaling and angiogenesis

Weiye Wang et al. Int J Cardiol. .

Abstract

Growth factors and their downstream receptor tyrosine kinases (RTKs) mediate a number of biological processes controlling cell function. Adaptor (docking) proteins, which consist exclusively of domains and motifs that mediate molecular interactions, link receptor activation to downstream effectors. Recent studies have revealed that Grb2-associated-binders (Gab) family members (including Gab1, Gab2, and Gab3), when phosphorylated on tyrosine residues, provide binding sites for multiple effector proteins, such as Src homology-2 (SH2)-containing protein tyrosine phosphatase 2 (SHP2) and phosphatidylinositol 3-kinase (PI3K) regulatory subunit p85, thereby playing important roles in transducing RTKs-mediated signals into pathways with diversified biological functions. Here, we provide an up-to-date overview on the domain structure and biological functions of Gab1, the most intensively studied Gab family protein, in growth factor signaling and biological functions, with a special focus on angiogenesis.

Keywords: Angiogenesis; Endothelial cells; Gab1; Receptor tyrosine kinase; Tyrosine phosphorylation.

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Figures

Figure 1
Figure 1. Domain structures of the Gab superfamily of adaptors/scaffolding proteins
The Gab family (Gab1, Gab2, and Gab3) is recruited by a wide variety of receptor tyrosine kinases (RTKs) and has multiple phosphorylation sites. Gab1, the most intensively-studied Gab family member, also contain serine and threonine phosphorylation sites, which negatively regulate HGF/Gab1 signaling. The Met-binding sequence (MBS, amino acid 487-499) within the Met-binding domain (MBD) in Gab1 is indicated with a red star. This specific MBS is absent in Gab2 and Gab3. P, proline-rich domain contains binding site for SH3 domain; motifs in red contain potential tyrosine phosphorylation sites for binding SHP-2 tyrosine phosphatase; motifs in blue contain potential tyrosine phosphorylation sites for binding PI3-K
Figure 2
Figure 2. Schematic representation of the role of Gab1 in growth factor signaling and angiogenesis
Growth factors, such as VEGF and HGF stimulate respective receptors on the ECs. Activation of the receptors is associated with phosphorylation of Gab1 and induction of signaling cascades dependent on association of Gab1 with either PI3K (represented by p110/p85 subunits) or the phosphatase SHP2. Downstream targets include Akt (downstream of PI3K), PKA/eNOS, ERK1/2/Egr1, and ERK5/KLF2 (all downstream of SHP2). These signaling pathways stimulate EC survival, proliferation, migration, stabilization, and tube formation, thereby contributing to angiogenesis. Collectively, Gab1 serves as the common regulator of ischemia-dependent angiogenesis. Abbreviations: Egr1, early growth response 1; eNOS, endothelial nitric oxide synthase; FGF2, fibroblast growth factor-2; Gab1-ecKO, endothelial cell-specific Gab1 knockout; HGF; hepatocyte growth factor; HLI, hindlimb ischemia; KLF2, kruppel-like factor 2; VEGF, vascular endothelial growth factor
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