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Published online 16 January 2001. doi:10.1083/jcb.152.2.263
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© The Rockefeller University Press, 0021-9525/2001/1/263/ $5.00
The Journal of Cell Biology, Volume 152, Number 2, January 22, 2001 263-274

Original Article

Activation of Endogenous Thrombin Receptors Causes Clustering and Sensitization of Epidermal Growth Factor Receptors of Swiss 3T3 Cells without Transactivation

Michael F. Croucha, Deborah A. Davya, Francis S. Willarda, and Leise A. Bervena
a Molecular Signaling Group, John Curtin School of Medical Research, Australian National University, Canberra, A.C.T. 2601, Australia

Correspondence to: Michael F. Crouch, Division of Neuroscience, John Curtin School of Medical Research, Australian National University, GPO Box 334, Canberra, A.C.T. 2601, Australia. Tel:61-2-62798391 Fax:61-2-62492687 E-mail:michael.crouch{at}anu.edu.au.

The G protein–coupled thrombin receptor can induce cellular responses in some systems by transactivating the epidermal growth factor (EGF) receptor. This is in part due to the stimulation of ectoproteases that generate EGF receptor ligands. We show here that this cannot account for the stimulation of proliferation or migration by thrombin of Swiss 3T3 cells. Thrombin has no direct effect on the activation state of the EGF receptor or of its downstream effectors. However, thrombin induces the subcellular clustering of the EGF receptor at filamentous actin–containing structures at the leading edge and actin arcs of migrating cells in association with other signaling molecules, including Shc and phospholipase C{gamma}1. In these thrombin-primed cells, the subsequent migratory response to EGF is potentiated. Thrombin did not potentiate the EGF-stimulated EGF receptor phosphorylation. Thus, in Swiss 3T3 cells the G protein–coupled thrombin receptor can potentiate the EGF tyrosine kinase receptor response when activated by EGF, and this appears to be due to the subcellular concentration of the receptor with downstream effectors and not to the overall ability of EGF to induce receptor transphosphorylation. Thus, the EGF receptor subcellular localization which is altered by thrombin appears to be an important determinant of the efficacy of downstream EGF receptor signaling in cell migration.

Key Words: costimulation, rafts, G protein, actin arc, crosstalk


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