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

Authors

Daniel N. Streblow, Oregon Health Sciences University
Jennifer Totonchy, Chapman UniversityFollow
Patsy Smith, Oregon Health Sciences University
Ryan Melnychuk, Oregon Health Sciences University
Laurel Hall, Oregon Health Sciences University
Dora Pancheva, Oregon Health Sciences University
Martine Smit, Leiden/Amsterdam Center for Drug Research
Paola Casarosa, Leiden/Amsterdam Center for Drug Research
David D. Schlaepfer, The Scripps Research Institute
Jay A. Nelson, Oregon Health Sciences University

Document Type

Article

Publication Date

2003

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 proteintyrosine 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.

Comments

This article was originally published in Journal of Biological Chemistry, volume 278, issue 50, in 2003. DOI: 10.1074/jbc.M307936200

Recommended Citation

Streblow DN, Vomaske J, Smith P, et al. Human cytomegalovirus chemokine receptor US28-induced smooth muscle cell migration is mediated by focal adhesion kinase and Src. J Biol Chem. 2003; 278(50):50456-65. doi: 10.1074/jbc.M307936200

Copyright

American Society for Biochemistry and Molecular Biology