Recruitment of Pyk2 to SHPS-1 signaling complex is required for IGF-I-dependent mitogenic signaling in vascular smooth muscle cells.
In vascular smooth muscle cells, IGF-I stimulates SHPS-1/SHP2/Src complex formation which is required for IGF-I-stimulated cell proliferation. Using SHP2/Src silencing and a Pyk2/Y402F mutant, we showed that Pyk2 was also recruited to the SHPS-1 complex. Pyk2 recruitment to SHPS-1 is mediated via the interaction of Pyk2 Tyr402 and the Src in response to IGF-I. Following Src/Pyk2 association, Src phosphorylates Pyk2 on Tyr881 providing a binding site for Grb2. Cells expressing Pyk2/Y881F showed decreased Grb2 recruitment to SHPS-1 and impaired Shc/Grb2 association. This change led to reduced Erk1/2 (MAP kinase) activation and cell proliferation in response to IGF-I. Our results show that, following its recruitment to the SHPS-1 signaling complex, Pyk2 localizes Grb2 in close proximity to Shc thereby facilitating Shc/Grb2 association which leads to Erk1/2 activation in response to IGF-I. Thus, Pyk2 recruitment to SHPS-1 plays an important role in regulating the IGF-I-stimulated mitogenic response.
Shen
Xinchun
X
Department of Medicine, University of North Carolina, Chapel Hill, 27599, USA.
Xi
Gang
G
Radhakrishnan
Yashwanth
Y
Clemmons
David R
DR
D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D051418:Focal Adhesion Kinase 2 / Q000235:genetics / Q000378:metabolism*; D051380:GRB2 Adaptor Protein / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000378:metabolism*; D015398:Signal Transduction; D013552:Swine
D000943:Antigens, Differentiation; D051380:GRB2 Adaptor Protein; D007334:Insulin-Like Growth Factor I; D051418:Focal Adhesion Kinase 2