An endogenous inhibitor of focal adhesion kinase blocks Rac1/JNK but not Ras/ERK-dependent signaling in vascular smooth muscle cells.
Humoral factors and extracellular matrix are critical co-regulators of smooth muscle cell (SMC) migration and proliferation. We reported previously that focal adhesion kinase (FAK)-related non-kinase (FRNK) is expressed selectively in SMC and can inhibit platelet-derived growth factor BB homodimer (PDGF-BB)-induced proliferation and migration of SMC by attenuating FAK activity. The goal of the current studies was to identify the mechanism by which FAK/FRNK regulates SMC growth and migration in response to diverse mitogenic signals. Transient overexpression of FRNK in SMC attenuated autophosphorylation of FAK at Tyr-397, reduced Src family-dependent tyrosine phosphorylation of FAK at Tyr-576, Tyr-577, and Tyr-881, and reduced phosphorylation of the FAK/Src substrates Cas and paxillin. However, FRNK expression did not alter the magnitude or dynamics of ERK activation induced by PDGF-BB or angiotensin II. Instead, FRNK expression markedly attenuated PDGF-BB-, angiotensin II-, and integrin-stimulated Rac1 activity and attenuates downstream signaling to JNK. Importantly, constitutively active Rac1 rescued the proliferation defects in FRNK expressing cells. Based on these observations, we hypothesize that FAK activation is required to integrate integrin signals with those from receptor tyrosine kinases and G protein-coupled receptors through downstream activation of Rac1 and that in SMC, FRNK may control proliferation and migration by buffering FAK-dependent Rac1 activation.
Sundberg
Liisa J
LJ
Department of Pathology, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
Galante
Lisa M
LM
Bill
Heather M
HM
Mack
Christopher P
CP
Taylor
Joan M
JM
D000256:Adenoviridae / Q000235:genetics; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology; D000077214:Becaplermin; D015153:Blotting, Western; D001973:Bromodeoxyuridine / Q000494:pharmacology; D019556:COS Cells; D002455:Cell Division; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement; D002478:Cells, Cultured; D029563:Cellular Apoptosis Susceptibility Protein / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D005982:Glutathione Transferase / Q000378:metabolism; D049452:Green Fluorescent Proteins; D007150:Immunohistochemistry; D008164:Luminescent Proteins / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008954:Models, Biological; D009130:Muscle, Smooth / Q000378:metabolism*; D051419:Paxillin; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D011233:Precipitin Tests; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology*; D020574:Proto-Oncogene Proteins c-sis; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013778:Tetrazolium Salts / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D014443:Tyrosine / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
C110656:2-(4-iodophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium; D029563:Cellular Apoptosis Susceptibility Protein; D003598:Cytoskeletal Proteins; D008164:Luminescent Proteins; D051419:Paxillin; D010750:Phosphoproteins; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; C496063:Pxn protein, rat; D011993:Recombinant Fusion Proteins; D013778:Tetrazolium Salts; D000804:Angiotensin II; D049452:Green Fluorescent Proteins; D000077214:Becaplermin; D014443:Tyrosine; D005982:Glutathione Transferase; C113183:FAK-related nonkinase; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496052:Ptk2 protein, rat; D020928:Mitogen-Activated Protein Kinases; D020830:rac1 GTP-Binding Protein; D001973:Bromodeoxyuridine