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© The Rockefeller University Press, 0021-9525/1999//1077 $5.00
The Journal of Cell Biology, Volume 145, Number 5, , 1999 1077-1088

Regular Articles

R-Ras Signals through Specific Integrin {alpha} Cytoplasmic Domains to Promote Migration and Invasion of Breast Epithelial Cells



Patricia J. Keely*,§, Elena V. Rusyn{ddagger},§, Adrienne D. Cox*,{ddagger},§, and Leslie V. Parise*,§

* Department of Pharmacology, {ddagger} Department of Radiation Oncology, and § Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599

Specificity and modulation of integrin function have important consequences for cellular responses to the extracellular matrix, including differentiation and transformation. The Ras-related GTPase, R-Ras, modulates integrin affinity, but little is known of the signaling pathways and biological functions downstream of R-Ras. Here we show that stable expression of activated R-Ras or the closely related TC21 (R-Ras 2) induced integrin-mediated migration and invasion of breast epithelial cells through collagen and disrupted differentiation into tubule structures, whereas dominant negative R-Ras had opposite effects. These results imply novel roles for R-Ras and TC21 in promoting a transformed phenotype and in the basal migration and polarization of these cells. Importantly, R-Ras induced an increase in cellular adhesion and migration on collagen but not fibronectin, suggesting that R-Ras signals to specific integrins. This was further supported by experiments in which R-Ras enhanced the migration of cells expressing integrin chimeras containing the {alpha}2, but not the {alpha}5, cytoplasmic domain. In addition, a transdominant inhibition previously noted only between integrin β cytoplasmic domains was observed for the {alpha}2 cytoplasmic domain; {alpha}2β1-mediated migration was inhibited by the expression of excess {alpha}2 but not {alpha}5 cytoplasmic domain-containing chimeras, suggesting the existence of limiting factors that bind the integrin {alpha} subunit. Using pharmacological inhibitors, we found that R-Ras induced migration on collagen through a combination of phosphatidylinositol 3-kinase and protein kinase C, but not MAPK, which is distinct from the other Ras family members, Rac, Cdc42, and N- and K-Ras. Thus, R-Ras communicates with specific integrin {alpha} cytoplasmic domains through a unique combination of signaling pathways to promote cell migration and invasion.

Key Words: integrins • Ras • cell migration • transformation • signaling

Abbreviations used in this paper: MAPK, mitogen-activated protein kinase; MEK, MAPK kinase; PI3K, phosphatidylinositol 3-kinase; PI4K, phosphatidylinositol 4-kinase; PKC, protein kinase C.


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