title: Suppression of c-Cbl tyrosine phosphorylation inhibits neointimal formation in balloon-injured rat arteries.
abstract: BACKGROUND
  c-Cbl, a ubiquitously expressed protooncogene, is tyrosine phosphorylated in response to a variety of stimuli, including growth factors such as platelet-derived growth factor (PDGF), and consequently activates signaling proteins such as phosphatidylinositol-3 kinase (PI3K) and Akt. In the present study, we examined the role of c-Cbl tyrosine phosphorylation in vascular injury.
  
  
  RESULTS
  Western blotting showed that the tyrosine phosphorylation of c-Cbl was increased in balloon-injured rat carotid arteries and in cultured smooth muscle cells on stimulation by PDGF-BB, followed by the activations of Akt and the mammalian target of rapamycin. Adenovirus-mediated overexpression of a c-Cbl mutant that ablates the major tyrosine phosphorylation sites attenuated the Akt and the mammalian target of rapamycin activation and decreased the proliferation and migration of smooth muscle cells in response to PDGF-BB or fibroblast growth factor. These effects could be reversed by constitutively active PI3K or Akt, suggesting that c-Cbl phosphorylation promotes the PDGF-BB-induced proliferation and migration of smooth muscle cells through the PI3K/Akt pathways. In addition, overexpression of c-Cbl-m increased the ubiquitination of the PDGF and fibroblast growth factor receptors. Importantly, in balloon-injured rat carotid arteries, local delivery of c-Cbl-m reduced the phosphorylation of Akt and the mammalian target of rapamycin, inhibited the migration and proliferation of smooth muscle cells, and prevented neointimal hyperplasia.
  
  
  CONCLUSIONS
  Our results demonstrate a novel role of c-Cbl in vascular remodeling after injury and suggest that modulation of c-Cbl tyrosine phosphorylation may be a therapeutic approach to treat vascular neointimal hyperplasia such as restenosis after angioplasty.
authors.affiliation: Institute of Cardiovascular Science, Peking University Health Science Center, Beijing 100083, China.
authors.forename: Zhihui
authors.initials: Z
authors.lastname: Tang
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Yanbo
authors.initials: Y
authors.lastname: Fan
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhu
authors.forename: Shu
authors.initials: S
authors.lastname: Chien
authors.forename: Nanping
authors.initials: N
authors.lastname: Wang
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000494:pharmacology; D000818:Animals; D000077214:Becaplermin; D002339:Carotid Arteries / Q000166:cytology / Q000378:metabolism*; D002404:Catheterization / Q000009:adverse effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005346:Fibroblast Growth Factors / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D050721:Proto-Oncogene Proteins c-cbl / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D020574:Proto-Oncogene Proteins c-sis; D051381:Rats; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases; D017539:Tunica Intima / Q000166:cytology / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism
chemical_list: D043925:Angiogenesis Inducing Agents; D000077214:Becaplermin; D005346:Fibroblast Growth Factors; D019869:Phosphatidylinositol 3-Kinases; D010982:Platelet-Derived Growth Factor; D011494:Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D050721:Proto-Oncogene Proteins c-cbl; D020574:Proto-Oncogene Proteins c-sis; D017468:Receptors, Fibroblast Growth Factor; D017479:Receptors, Platelet-Derived Growth Factor; D058570:TOR Serine-Threonine Kinases; D014443:Tyrosine; C546845:mTOR protein, rat