title: Docking protein Gab1 is an essential component of postnatal angiogenesis after ischemia via HGF/c-met signaling.
abstract: BACKGROUND
  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.
  
  
  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 signal-regulated kinase (ERK)1/2 pathway and for HGF-induced stabilization of ECs via ERK5. In contrast, Gab1-p85 complex regulated activation of AKT and contributed partially to migration of ECs after HGF stimulation. Microarray analysis demonstrated that HGF upregulated angiogenesis-related genes such as KLF2 (Krüppel-like factor 2) and Egr1 (early growth response 1) via Gab1-SHP2 complex in human ECs. In Gab1ECKO mice, gene transfer of vascular endothelial growth factor, but not HGF, improved blood flow recovery and ameliorated limb necrosis after HLI.
  
  
  CONCLUSIONS
  Gab1 is essential for postnatal angiogenesis after ischemia via HGF/c-Met signaling.
authors.affiliation: Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Shioyama
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Nakaoka
authors.forename: Kaori
authors.initials: K
authors.lastname: Higuchi
authors.forename: Takashi
authors.initials: T
authors.lastname: Minami
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Taniyama
authors.forename: Keigo
authors.initials: K
authors.lastname: Nishida
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Kidoya
authors.forename: Takashi
authors.initials: T
authors.lastname: Sonobe
authors.forename: Hisamichi
authors.initials: H
authors.lastname: Naito
authors.forename: Yoh
authors.initials: Y
authors.lastname: Arita
authors.forename: Takahiro
authors.initials: T
authors.lastname: Hashimoto
authors.forename: Tadashi
authors.initials: T
authors.lastname: Kuroda
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Fujio
authors.forename: Mikiyasu
authors.initials: M
authors.lastname: Shirai
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Takakura
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Morishita
authors.forename: Keiko
authors.initials: K
authors.lastname: Yamauchi-Takihara
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Kodama
authors.forename: Toshio
authors.initials: T
authors.lastname: Hirano
authors.forename: Naoki
authors.initials: N
authors.lastname: Mochizuki
authors.forename: Issei
authors.initials: I
authors.lastname: Komuro
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000831:Animals, Newborn; D001158:Arteries / Q000254:growth & development; D002352:Carrier Proteins / Q000378:metabolism*; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D017228:Hepatocyte Growth Factor / Q000378:metabolism* / Q000494:pharmacology; D006614:Hindlimb / Q000098:blood supply*; D006801:Humans; D007511:Ischemia / Q000150:complications*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000209:etiology* / Q000503:physiopathology; D010750:Phosphoproteins / Q000172:deficiency / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D012039:Regional Blood Flow; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases / Q000378:metabolism; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C551587:Cmip protein, mouse; C490897:Gab1 protein, mouse; C490894:Gab2 protein, mouse; D010750:Phosphoproteins; D014443:Tyrosine; D017228:Hepatocyte Growth Factor; D058543:Class Ia Phosphatidylinositol 3-Kinase; D048049:Extracellular Signal-Regulated MAP Kinases; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases