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Molecular and Cellular Biology, August 2009, p. 4508-4518, Vol. 29, No. 16
0270-7306/09/$08.00+0     doi:10.1128/MCB.00015-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Cell Migration Is Regulated by Platelet-Derived Growth Factor Receptor Endocytosis{triangledown} ,{dagger}

Kenji Kawada,1 Geeta Upadhyay,1 Sébastien Ferandon,2,3 Sailajah Janarthanan,1 Matthew Hall,1 Jean-Pierre Vilardaga,2,3,4 and Vijay Yajnik1*

Gastrointestinal Unit,1 Endocrine Unit,2 Center for Systems Biology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114,3 Department of Pharmacology and Chemical Biology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 152134

Received 5 January 2009/ Returned for modification 4 March 2009/ Accepted 2 June 2009

Cell migration requires spatial and temporal processes that detect and transfer extracellular stimuli into intracellular signals. The platelet-derived growth factor (PDGF) receptor is a cell surface receptor on fibroblasts that regulates proliferation and chemotaxis in response to PDGF. How the PDGF signal is transmitted accurately through the receptor into cells is an unresolved question. Here, we report a new intracellular signaling pathway by which DOCK4, a Rac1 guanine exchange factor, and Dynamin regulate cell migration by PDGF receptor endocytosis. We showed by a series of biochemical and microscopy techniques that Grb2 serves as an adaptor protein in the formation of a ternary complex between the PDGF receptor, DOCK4, and Dynamin, which is formed at the leading edge of cells. We found that this ternary complex regulates PDGF-dependent cell migration by promoting PDGF receptor endocytosis and Rac1 activation at the cell membrane. This study revealed a new mechanism by which cell migration is regulated by PDGF receptor endocytosis.

* Corresponding author. Mailing address: Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, GRJ 825, 55 Fruit St., Boston, MA 02114. Phone: (617) 726-1306. Fax: (617) 726-3673. E-mail: vyajnik{at}partners.org

{triangledown} Published ahead of print on 15 June 2009.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, August 2009, p. 4508-4518, Vol. 29, No. 16
0270-7306/09/$08.00+0     doi:10.1128/MCB.00015-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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