Portal de Periódicos da CAPES

The Gift of Gab1 (Grb-2-Associated Binder 1)

2011; Lippincott Williams & Wilkins; Volume: 31; Issue: 5 Linguagem: Inglês

10.1161/atvbaha.111.225987

1524-4636

Catherine A. Lemarié, Stéphanie Lehoux,

Protease and Inhibitor Mechanisms

HomeArteriosclerosis, Thrombosis, and Vascular BiologyVol. 31, No. 5The Gift of Gab1 (Grb-2-Associated Binder 1) Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBThe Gift of Gab1 (Grb-2-Associated Binder 1) Catherine A. Lemarié and Stéphanie Lehoux Catherine A. LemariéCatherine A. Lemarié From Lady Davis Institute, McGill University, Montreal, Quebec, Canada. and Stéphanie LehouxStéphanie Lehoux From Lady Davis Institute, McGill University, Montreal, Quebec, Canada. Originally published1 May 2011https://doi.org/10.1161/ATVBAHA.111.225987Arteriosclerosis, Thrombosis, and Vascular Biology. 2011;31:956–957Ischemia-induced neovascularization is critical for blood flow recovery and tissue repair in hypoxic conditions. It occurs via extension or remodeling of existing blood vessels, observed throughout development and into adulthood.1 The angiogenic process is driven by growth factors emanating from the zone of ischemia, leading to the activation, proliferation, and migration of endothelial cells (ECs), which lie at the forefront of the expanding vasculature (Figure).2 Angiogenesis is involved in many physiological and pathological settings, such as ischemia, atherosclerosis, diabetes, and cancer, making it an attractive therapeutic target.Download figureDownload PowerPointFigure. Gab1 as the common modulator of ischemia-dependent angiogenesis. Hypoxic tissues release growth factors, such as VEGF, HGF, and neuregulin, that enter the circulation and stimulate specific receptors on the ECs (inset). Activation of the receptors is associated with phosphorylation (P) of Gab1 and induction of signaling cascades dependent on interaction of Gab1 with either phosphatidylinositol 3-kinase (represented by p110/p85 subunits) or the phosphatase Shp2. Downstream targets include Akt, protein kinase A (PKA), endothelial nitric oxide synthase (eNOS), ERK1/2, ERK5, and Krüppel-like factor 2 (KLF2). These pathways may all contribute to angiogenesis by stimulating EC survival, proliferation, migration, and tube formation. VEGFR indicates VEGF receptor.See accompanying article on page 1016Of the many growth factors and related signaling networks that have been shown to regulate EC function and angiogenesis, vascular endothelial growth factor (VEGF) might be the best defined.3 VEGF activates Akt and endothelial nitric oxide synthase, crucial pathways in postnatal angiogenesis.4 Similar signaling pathways have been attributed to hepatocyte growth factor (HGF), which has recently emerged as another potent mediator of angiogenesis. One common denominator uniting the VEGF and HGF responses is binding of their receptors to Grb-2-associated binder 1 (Gab1). Gab1 is highly expressed in ECs, and it is essential for receptor tyrosine kinase–dependent promotion of cell migration, survival, and tube formation.5–9Gab1 belongs to the scaffolding adaptor protein family. It has an N-terminal pleckstrin homology domain, as well as multiple tyrosine-based motifs and proline-rich sequences, which are potential binding sites for Src homology 2 and 3 domains, respectively. Gab1 undergoes tyrosine phosphorylation upon cell stimulation with various growth factors, cytokines, G protein-coupled receptor agonists, and immunoantigens10,11 Tyrosine-phosphorylated Gab1 provides docking sites for Src homology 2 domain–containing signaling molecules, such as the protein-tyrosine phosphatase protein tyrosine phosphatase, non receptor type II (SHP2), phosphatidylinositol 3-kinase regulatory subunit p85, phospholipase C-γ, Crk, and Ras GTPase-activating protein.10Gab1 can be recruited to activated receptors through direct or indirect mechanisms. Direct recruitment has been demonstrated only for interaction between Gab1 and c-Met (the receptor for HGF).12 However, Gab1 has been shown to interact indirectly with a number of receptor tyrosine kinases relevant to the cardiovascular system, such as the ErbB receptors of neuregulin-1β,13 and VEGF receptor 2.14 Gab1 has also been involved in shear stress–dependent activation of protein kinase A, upstream of endothelial nitric oxide production.15In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Zhao et al directly demonstrate a role for Gab1 in regulating postnatal angiogenesis in vivo and in vitro.16 In fact, the authors of this article and 2 other groups17,18 simultaneously generated Gab1-endothelial cell-specific Gab1 knockout mice using an endothelial-specific cre-lox approach. The animals are viable and have no obvious vascular defects, indicating that endothelial Gab1 is not involved in developmental vasculogenesis. All 3 groups demonstrated that Gab1-ecKO mice have inadequate angiogenesis after hindlimb ischemia: 2 weeks after the femoral artery resection, blood flow and capillary density in the gastrocnemius muscle remain low compared with wild-type mice, which is associated with limb necrosis.16The dramatic decrease in capillary density in Gab1-ecKO mice suggested that EC survival may be compromised. Indeed, Zhao et al16 report that apoptotic ECs are more abundant in the gastrocnemius muscle from Gab1-ecKO mice than in wild-type mice after ischemia. VEGF and HGF are potent prosurvival factors,19 and Zhao et al observed that levels of both growth factors are increased in ischemic hindlimb muscles. However, the viability of Gab1-deficient ECs cannot be maintained by either growth factor in vitro, whereas wild-type cells are protected from death. One possible explanation is supplied by Shioyama et al.18 They demonstrated that in ECs overexpressing Gab1, HGF specifically upregulates the mRNA and protein expression of Krüppel-like factor 2. Krüppel-like factor 2 is an important antiapoptotic agent, acting in part through endothelial nitric oxide synthase activation,20,21 and it could mediate the Gab1-dependent protective effect of HGF in ECs.A thorough understanding of signaling pathways underlying postnatal angiogenesis is crucial in designing new treatment for human ischemic diseases. Zhao et al demonstrated that Gab1 is necessary for HGF-induced Akt and extracellular signal-regulated kinase (ERK) 1/2 phosphorylation through phosphatidylinositol 3-kinase and SHP2 activation, respectively.16 Shioyama et al completed those findings, showing that ERK5 is also activated downstream of Gab1-SHP2 after HGF stimulation.18 Furthermore, Lu et al found that Gab1 is also required for Akt activation in VEGF-induced angiogenesis and identified an important protein kinase A–dependent pathway for VEGF-induced endothelial nitric oxide synthase activation.17Taken together, the evidence provided by 3 different groups shows that endothelial Gab1 is crucial for HGF-and VEGF-induced postnatal angiogenesis. These studies suggested a possible cross-talk between VEGF and HGF, both growth factors using Gab1 as a signaling intermediate to activate ERK1/2 and Akt. These are key pathways involved in EC stabilization and migration and could account for the dramatic impairment of angiogenic processes in Gab1-ecKO mice. A logical follow-up question will be to address the role of Gab1 in matrix metalloproteinase activation and vascular remodeling, which are required for EC detachment from extracellular matrix and migration in angiogenesis.FootnotesCorrespondence to Lady Davis Institute, McGill University, 3755 Cote Ste Catherine, Montreal, Quebec H3T 1E2, Canada. E-mail stephanie.[email protected]caReferences1. Ferguson JE, Kelley RW, Patterson C. Mechanisms of endothelial differentiation in embryonic vasculogenesis. Arterioscler Thromb Vasc Biol. 2005; 25:2246–2254. LinkGoogle Scholar2. Carmeliet P. Angiogenesis in health and disease. Nat Med. 2003; 9:653–660. CrossrefMedlineGoogle Scholar3. Carmeliet P. Mechanisms of angiogenesis and arteriogenesis. Nat Med. 2000; 6:389–395. CrossrefMedlineGoogle Scholar4. Murohara T, Asahara T, Silver M, Bauters C, Masuda H, Kalka C, Kearney M, Chen D, Symes JF, Fishman MC, Huang PL, Isner JM. Nitric oxide synthase modulates angiogenesis in response to tissue ischemia. J Clin Invest. 1998; 101:2567–2578. CrossrefMedlineGoogle Scholar5. Dance M, Montagner A, Yart A, Masri B, Audigier Y, Perret B, Salles JP, Raynal P. The adaptor protein Gab1 couples the stimulation of vascular endothelial growth factor receptor-2 to the activation of phosphoinositide 3-kinase. J Biol Chem. 2006; 281:23285–23295. CrossrefMedlineGoogle Scholar6. Laramee M, Chabot C, Cloutier M, Stenne R, Holgado-Madruga M, Wong AJ, Royal I. The scaffolding adapter Gab1 mediates vascular endothelial growth factor signaling and is required for endothelial cell migration and capillary formation. J Biol Chem. 2007; 282:7758–7769. CrossrefMedlineGoogle Scholar7. Rodrigues GA, Falasca M, Zhang Z, Ong SH, Schlessinger J. A novel positive feedback loop mediated by the docking protein Gab1 and phosphatidylinositol 3-kinase in epidermal growth factor receptor signaling. Mol Cell Biol. 2000; 20:1448–1459. CrossrefMedlineGoogle Scholar8. Cunnick JM, Dorsey JF, Munoz-Antonia T, Mei L, Wu J. Requirement of Shp2 binding to Grb2-associated binder-1 for mitogen-activated protein kinase activation in response to lysophosphatidic acid and epidermal growth factor. J Biol Chem. 2000; 275:13842–13848. CrossrefMedlineGoogle Scholar9. Laffargue M, Raynal P, Yart A, Peres C, Wetzker R, Roche S, Payrastre B, Chap H. An epidermal growth factor receptor/Gab1 signaling pathway is required for activation of phosphoinositide 3-kinase by lysophosphatidic acid. J Biol Chem. 1999; 274:32835–32841. CrossrefMedlineGoogle Scholar10. Gu H, Neel BG. The "Gab" in signal transduction. Trends Cell Biol. 13:122–130, 2003. CrossrefMedlineGoogle Scholar11. Nishida K, Hirano T. The role of Gab family scaffolding adapter proteins in the signal transduction of cytokine and growth factor receptors. Cancer Sci. 2003; 94:1029–1033. CrossrefMedlineGoogle Scholar12. Weidner KM, Di Cesare S, Sachs M, Brinkmann V, Behrens J, Birchmeier W. Interaction between Gab1 and the c-met receptor tyrosine kinase is responsible for epithelial morphogenesis. Nature. 1996; 384:173–176. CrossrefMedlineGoogle Scholar13. Nakaoka Y, Nishida K, Narimatsu M, Kamiya A, Minami T, Sawa H, Okawa K, Fujio Y, Koyama T, Maeda M, Sone M, Yamasaki S, Arai Y, Koh GY, Kodama T, Hirota H, Otsu K, Hirano T, Mochizuki N. Gab family proteins are essential for postnatal maintenance of cardiac function via neuregulin-1/ErbB signaling. J Clin Invest. 2007; 117:1771–1781. CrossrefMedlineGoogle Scholar14. Caron C, Spring K, Laramee M, Chabot C, Cloutier M, Gu H, Royal I. Non-redundant roles of the Gab1 and Gab2 scaffolding adapters in VEGF-mediated signalling, migration, and survival of endothelial cells. Cell Signal. 21:943–953, 2009. CrossrefMedlineGoogle Scholar15. Dixit M, Loot AE, Mohamed A, Fisslthaler B, Boulanger CM, Ceacareanu B, Hassid A, Busse R, Fleming I. Gab1, SHP2, and protein kinase A are crucial for the activation of the endothelial no synthase by fluid shear stress. Circ Res. 2005; 97:1236–1244. LinkGoogle Scholar16. Zhao J, Wang W, Ha CH, Kim JY, Wong C, Redmond EM, Hamik A, Jain MK, Feng G-S, Jin ZG. Endothelial Grb2-associated binder 1 is crucial for postnatal angiogenesis. Arterioscler Thromb Vasc Biol. 20111016–1023. LinkGoogle Scholar17. Lu Y, Xiong Y, Huo Y, Han J, Yang X, Zhang R, Zhu DS, Klein-Hessling S, Li J, Zhang X, Han X, Li Y, Shen B, He Y, Shibuya M, Feng GS, Luo J. Grb-2-associated binder 1 (Gab1) regulates postnatal ischemic and VEGF-induced angiogenesis through the protein kinase A-endothelial NOS pathway. Proc Natl Acad Sci U S A. 2011; 108:2957–2962. CrossrefMedlineGoogle Scholar18. Shioyama W, Nakaoka Y, Higuchi K, Minami T, Taniyama Y, Nishida K, Kidoya H, Sonobe T, Naito H, Arita Y, Hashimoto T, Kuroda T, Fujio Y, Shirai M, Takakura N, Morishita R, Yamauchi-Takihara K, Kodama T, Hirano T, Mochizuki N, Komuro I. Docking protein Gab1 is an essential component of postnatal angiogenesis after ischemia via HGF/c-Met signaling. Circ Res. 2011[Epub ahead of print]. LinkGoogle Scholar19. Bardelli A, Longati P, Albero D, Goruppi S, Schneider C, Ponzetto C, Comoglio PM. HGF receptor associates with the anti-apoptotic protein BAG-1 and prevents cell death. EMBO J. 1996; 15:6205–6212. CrossrefMedlineGoogle Scholar20. Atkins GB, Jain MK. Role of Krüppel-like transcription factors in endothelial biology. Circ Res. 2007; 100:1686–1695. LinkGoogle Scholar21. Nicoli S, Standley C, Walker P, Hurlstone A, Fogarty KE, Lawson ND. MicroRNA-mediated integration of haemodynamics and VEGF signalling during angiogenesis. Nature. 2010; 464:1196–1200. CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Ye M, Guo X, Kan K, Ni Q, Chen J, Wang H, Qian X, Xue G, Deng H and Zhang L (2021)(2020) Loss of GRB2 associated binding protein 1 in arteriosclerosis obliterans promotes host autophagy, Chinese Medical Journal, 10.1097/CM9.0000000000001255, 134:1, (73-80) Hu L and Liu R (2016) Expression of Gab1 Is Associated with Poor Prognosis of Patients with Epithelial Ovarian Cancer, The Tohoku Journal of Experimental Medicine, 10.1620/tjem.239.177, 239:3, (177-184), . Wang W, Xu S, Yin M and Jin Z (2015) Essential roles of Gab1 tyrosine phosphorylation in growth factor-mediated signaling and angiogenesis, International Journal of Cardiology, 10.1016/j.ijcard.2014.10.148, 181, (180-184), Online publication date: 1-Feb-2015. Zhang X, Zhang Y, Tao B, Wang D, Cheng H, Wang K, Zhou R, Xie Q and Ke Y (2012) Docking protein Gab2 regulates mucin expression and goblet cell hyperplasia through TYK2/STAT6 pathway, The FASEB Journal, 10.1096/fj.12-211755, 26:11, (4603-4613), Online publication date: 1-Nov-2012. Powers A, Liu B, Lee A and Palecek S (2012) Macroporous hydrogel micropillars for quantifying Met kinase activity in cancer cell lysates, The Analyst, 10.1039/c2an35464k, 137:17, (4052), . May 2011Vol 31, Issue 5 Advertisement Article InformationMetrics © 2011 American Heart Association, Inc.https://doi.org/10.1161/ATVBAHA.111.225987PMID: 21508340 Originally publishedMay 1, 2011 Keywordsischemiaangiogenesisgrowth factorsnitric oxide synthaseendotheliumPDF download Advertisement