A role for PYK2 in regulation of ERK1/2 MAP kinases and PI 3-kinase by ANG II in vascular smooth muscle.
Abnormal vascular smooth muscle cell (VSMC) growth plays a key role in the pathogenesis of hypertension and atherosclerosis. Angiotensin II (ANG II) elicits a hypertrophic growth response characterized by an increase in protein synthesis without cell proliferation. The present study investigated the role of the nonreceptor tyrosine kinase PYK2 in the regulation of ANG II-induced signaling pathways that mediate VSMC growth. Using coimmunoprecipitation analysis, the role of PYK2 as an upstream regulator of both extracellular signal-related kinase (ERK) 1/2 mitogen-activated protein kinase and phosphatidylinositol 3-kinase (PI 3-kinase) pathways was examined in cultured rat aortic VSMC. ANG II (100 nM) promoted the formation of a complex between PYK2 and the ERK1/2 regulators Shc and Grb2. ANG II caused a rapid and Ca(2+)-dependent tyrosine phosphorylation of the adapter molecule p130Cas, which coimmunoprecipitated both PYK2 and PI 3-kinase in ANG II-treated VSMC. Complex formation between PI 3-kinase and p130Cas and PYK2 was associated with a rapid phosphorylation of the ribosomal p70(S6) kinase in a Ca(2+)- and tyrosine kinase-dependent manner. These data suggest that PYK2 is an important regulator of multiple signaling pathways involved in ANG II-induced VSMC growth.
Rocic
P
P
Department of Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
Govindarajan
G
G
Sabri
A
A
Lucchesi
P A
PA
D048868:Adaptor Proteins, Signal Transducing; D000804:Angiotensin II / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D050719:Crk-Associated Substrate Protein; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051418:Focal Adhesion Kinase 2; D051380:GRB2 Adaptor Protein; D006984:Hypertrophy / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000187:drug effects / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000187:drug effects / Q000378:metabolism*; D011506:Proteins / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin / Q000187:drug effects / Q000378:metabolism; D050717:Retinoblastoma-Like Protein p130; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D019061:src-Family Kinases / Q000187:drug effects / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; C493843:Bcar1 protein, rat; D002867:Chromones; D050719:Crk-Associated Substrate Protein; D004791:Enzyme Inhibitors; D051380:GRB2 Adaptor Protein; C495950:Grb2 protein, rat; D009025:Morpholines; D010750:Phosphoproteins; D011506:Proteins; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin; D050717:Retinoblastoma-Like Protein p130; D000804:Angiotensin II; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D051418:Focal Adhesion Kinase 2; C496054:Ptk2b protein, rat; D019061:src-Family Kinases; D019893:Ribosomal Protein S6 Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D002118:Calcium