Docking Protein Gab1 Is an Essential Component of Postnatal Angiogenesis After Ischemia via HGF/c-Met Signaling

Abstract

Rationale: Grb2-associated binder (Gab) docking proteins, consisting of Gab1, Gab2, and Gab3, have crucial roles in growth factor-dependent signaling. Various proangiogenic growth factors regulate angiogenesis and endothelial function. However, the roles of Gab proteins in angiogenesis remain elusive.Objective: To elucidate the role of Gab proteins in postnatal angiogenesis. Methods and Results: Endothelium-specific Gab1 knockout (Gab1ECKO) mice were viable and showed no obvious defects in vascular development. Therefore, we analyzed a hindlimb ischemia (HLI) model of control, Gab1ECKO, or conventional Gab2 knockout (Gab2KO) mice. Intriguingly, impaired blood flow recovery and necrosis in the operated limb was observed in all of Gab1ECKO, but not in control or Gab2KO mice. Among several proangiogenic growth factors, hepatocyte growth factor (HGF) induced the most prominent tyrosine phosphorylation of Gab1 and subsequent complex formation of Gab1 with SHP2 (Src homology-2-containing protein tyrosine phosphatase 2) and phosphatidylinositol 3-kinase subunit p85 in human endothelial cells (ECs). Gab1-SHP2 complex was required for HGF-induced migration and proliferation of ECs via extracellular

The Versatile Role of Gab1 in the Circulatory System

“…The resulting Gab1ECKO mice display impaired angiogenesis and enhanced necrosis in a hindlimb ischemia (HLI) model because of reduced HGF/c-Met signaling. 5 This finding is in agreement with another report showing that Gab1 is involved in ischemic and VEGF-induced angiogenesis using the same strategy for endothelial deletion of Gab1. 6 A third study using the Gab1ECKO mouse model further confirmed the requirement of Gab1 for postnatal angiogenesis.…”

“…This observation is in line with the established role of these transcription factors as antiinflammatory regulators in the vasculature, 10 and with a previous publication by the same group implicating Gab1 in HGF-mediated induction of KLF2. 5 The concept of enhanced vascular inflammation in the absence of endothelial Gab1 is further supported by the immunohistochemical analysis of the aortic tissue conducted in this study. 1 Double deficiency of Gab1 and ApoE in the angiotensin-II exposed endothelium increased both vascular cell adhesion molecule-1 (VCAM-1) expression and macrophage infiltration of aortic tissue, both involved in the initiation and progression of atherosclerosis.…”

“…So far, Gab1 has been implicated in vascular homeostasis and angiogenesis by several studies. [5][6][7] In that regard, it is interesting to note that tyrosine phosphorylation of Gab1 in endothelial cells can be induced by blood flow shear stress. 12 Likewise, Gab1 becomes tyrosine phosphorylated and complexed with the PI3K subunit p85 in angiotensin-II stimulated vascular smooth muscle cells, a process that most likely involves the transactivation of RTKs such as the epidermal growth factor receptor by the activated angiotensin-II receptor 1.…”

Arf6 regulates tumour angiogenesis and growth through HGF-induced endothelial β1 integrin recycling

“…It has been reported that HGF/cMet signalling in endothelial cells is involved in tumour angiogenesis and growth [9][10][11] . In addition, it has been demonstrated that the mice lacking endothelial expression of the cMet-docking protein Gab1, which mediates HGF/cMet signalling, exhibit no apparent defects in developmental angiogenesis, but show impairment in postnatal angiogenesis after ischaemia 40 . These observations indicate that endothelial HGF/ cMet signalling actively regulates pathological but not developmental angiogenesis.…”

Cardiac Gab1 deletion leads to dilated cardiomyopathy associated with mitochondrial damage and cardiomyocyte apoptosis

“…Our group and others have demonstrated that endothelial-specific Gab1 deficiency in mice impairs ischemia-induced angiogenesis. [16][17][18] Moreover, in contrast to the defects in cardiac development observed in Gab1 − / − mice, cardiomyocyte-specific Gab1 conditional knockout (Gab1-cKO) mice generated with the Cre-LoxP system are viable and display normal cardiac morphology at birth. 19 Gab protein family has three members, Gab1, Gab2 and Gab3.…”