Human Cytomegalovirus Chemokine Receptor US28-induced Smooth Muscle Cell Migration is Mediated by Focal Adhesion Kinase and Src

Daniel N. Streblow, Jennifer Vomaske, Patsy Smith, Ryan Melnychuk, Laurel Hall, Dora Pancheva, Martine Smit, Paola Casarosa, David D. Schlaepfer, Jay A. Nelson

Research output: Contribution to journalArticle

74 Scopus citations

Abstract

The human cytomegalovirus-encoded chemokine receptor US28 induces arterial smooth muscle cell (SMC) migration; however, the underlying mechanisms involved in this process are unclear. We have previously shown that US28-mediated SMC migration occurs by a ligand-dependent process that is sensitive to protein-tyrosine kinase inhibitors. We demonstrate here that US28 signals through the non-receptor protein-tyrosine kinases Src and focal adhesion kinase (FAK) and that this activity is necessary for US28-mediated SMC migration. In the presence of RANTES (regulated on activation normal T cell expressed and secreted), US28 stimulates the production of a FAK·Src kinase complex. Interestingly, Src co-immunoprecipitates with US28 in a ligand-dependent manner. This association occurs earlier than the formation of the FAK·Src kinase complex, suggesting that US28 activates Src before FAK. US28 binding to RANTES also promotes the formation of a Grb2·FAK complex, which is sensitive to treatment with the Src inhibitor PP2, further highlighting the critical role of Src in US28 activation of FAK. Human cytomegalovirus US28-mediated SMC migration is inhibited by treatment with PP2 and through the expression of either of two dominant negative inhibitors of FAK (F397Y and NH2-terminal amino acids 1-401). These findings demonstrate that activation of FAK and Src plays a critical role in US28-mediated signaling and SMC migration.

Original languageEnglish (US)
Pages (from-to)50456-50465
Number of pages10
JournalJournal of Biological Chemistry
Volume278
Issue number50
DOIs
StatePublished - Dec 12 2003

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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