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J. Cell Biol.,
Volume 145, Number 5, May 31, 1999 1077-1088
Cytoplasmic Domains to
Promote Migration and Invasion of Breast Epithelial Cells
§§
* Department of Pharmacology, 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 Department of Radiation Oncology, and § Lineberger Comprehensive Cancer Center,
University of North Carolina, Chapel Hill, North Carolina 27599
2,
but not the 5, cytoplasmic domain. In addition, a
transdominant inhibition previously noted only between integrin 
cytoplasmic domains was observed for
the 2 cytoplasmic domain; 21-mediated migration
was inhibited by the expression of excess 2 but not 5
cytoplasmic domain-containing chimeras, suggesting
the existence of limiting factors that bind the integrin
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 cytoplasmic domains through a unique combination of signaling pathways to promote cell migration
and invasion.
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