title: Novel role of proline-rich nonreceptor tyrosine kinase 2 in vascular wall remodeling after balloon injury.
abstract: OBJECTIVE
  To investigate the role of Pyk2, a proline-rich nonreceptor tyrosine kinase, in G protein-coupled receptor agonist, thrombin-induced human aortic smooth muscle cell growth and migration, and injury-induced vascular wall remodeling.
  
  
  RESULTS
  Thrombin, a G protein-coupled receptor agonist, activated Pyk2 in a time-dependent manner and inhibition of its stimulation attenuated thrombin-induced human aortic smooth muscle cell migration and proliferation. Thrombin also activated Grb2-associated binder protein 1, p115 Rho guanine nucleotide exchange factor, Rac1, RhoA, and p21-activated kinase 1 (Pak1) and interference with stimulation of these molecules attenuated thrombin-induced human aortic smooth muscle cell migration and proliferation. In addition, adenovirus-mediated expression of dominant negative Pyk2 inhibited thrombin-induced Grb2-associated binder protein 1, p115 rho guanine nucleotide exchange factor, Rac1, RhoA and Pak1 stimulation. Balloon injury also caused activation of Pyk2, Grb2-associated binder protein 1, p115 rho guanine nucleotide exchange factor, Rac1, RhoA, and Pak1 in the carotid artery of rat, and these responses were sensitive to inhibition by the dominant negative Pyk2. Furthermore, inhibition of Pyk2 activation resulted in reduced recruitment of smooth muscle cells onto the luminal surface and their proliferation in the intimal region leading to suppression of neointima formation.
  
  
  CONCLUSIONS
  Together, these results demonstrate for the first time that Pyk2 plays a crucial role in G protein-coupled receptor agonist thrombin-induced human aortic smooth muscle cell growth and migration, as well as balloon injury-induced neointima formation.
authors.affiliation: Department of Physiology, University of Tennessee Health Science Center, 894 Union Avenue, Memphis, TN 38163, USA.
authors.forename: Ravisekhar
authors.initials: R
authors.lastname: Gadepalli
authors.forename: Nikhlesh K
authors.initials: NK
authors.lastname: Singh
authors.forename: Venkatesh
authors.initials: V
authors.lastname: Kundumani-Sridharan
authors.forename: Mark R
authors.initials: MR
authors.lastname: Heckle
authors.forename: Gadiparthi N
authors.initials: GN
authors.lastname: Rao
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D020212:Carotid Artery Injuries / Q000201:enzymology* / Q000209:etiology / Q000235:genetics / Q000473:pathology; D017536:Carotid Artery, Common / Q000201:enzymology / Q000473:pathology; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004789:Enzyme Activation; D051418:Focal Adhesion Kinase 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D058426:Neointima; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D051381:Rats; D064067:Rho Guanine Nucleotide Exchange Factors; D015398:Signal Transduction / Q000187:drug effects; D013917:Thrombin / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D057772:Vascular System Injuries / Q000201:enzymology* / Q000209:etiology / Q000235:genetics / Q000473:pathology; D054462:p21-Activated Kinases / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C098587:GAB1 protein, human; D020662:Guanine Nucleotide Exchange Factors; D047428:Protein Kinase Inhibitors; C107953:RAC1 protein, human; D064067:Rho Guanine Nucleotide Exchange Factors; C066737:RHOA protein, human; D051418:Focal Adhesion Kinase 2; C103547:PTK2B protein, human; C496054:Ptk2b protein, rat; C515903:PAK1 protein, human; D054462:p21-Activated Kinases; D013917:Thrombin; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein