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Cdc42 and Rac1 induce integrin-mediated cell motility and invasiveness through PI(3)K

Nature volume 390, pages 632–636 (1997)Cite this article

Abstract

Transformation of mammary epithelial cells into invasive carcinoma results in alterations in their integrin-mediated responses to the extracellular matrix, including a loss of normal epithelial polarization and differentiation, and a switch to a more motile, invasive phenotype. Changes in the actin cytoskeleton associated with this switch suggest that the small GTPases Cdc42 and Rac, which regulate actin organization1,2, might modulate motility and invasion. However, the role of Cdc42 and Rac1 in epithelial cells, especially with respect to integrin-mediated events, has not been well characterized. Here we show that activation of Cdc42 and Rac1 disrupts the normal polarization of mammary epithelial cells in a collagenous matrix, and promotes motility and invasion. This motility does not require the activation of PAK, JNK, p70 S6 kinase, or Rho, but instead requires phosphatidylinositol-3-OH kinase (PI(3)K). Further, direct PI(3)K activation is sufficient to disrupt epithelial polarization and induce cell motility and invasion. PI(3)K inhibition also disrupts actin structures, suggesting that activation of PI(3)K by Cdc42 and Rac1 alters actin organization, leading to increased motility and invasiveness.

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Figure 1: Expression of activated Cdc42, Rac1 or PI(3)K disrupts the organized polarization of mammary epithelial cells.
Figure 2: Cdc42 and Rac induce motility and invasiveness.
Figure 3: Signaling pathways and effectors downstream of Cdc42 and Rac.
Figure 4: PI(3)K mediates Cdc42- and Rac-induced cell motility and invasion.
Figure 5: PI(3)K inhibition disrupts Cdc42- and Rac-induced spreading and formation of actin structures.

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Acknowledgements

We thank L. Van Aelst for the Rac1(12V) effector-domain plasmids and discussion; J. Downward for the p110(K227E) construct; J. Kwong and J. McCarthy for discussion; L. Graves for assistance with PI(3)K and S6 kinase assays; C. Bradham for assistance with JNK assays and Q. Lambert for technical assistance. This work was supported by grants from the Elsa Pardee Foundation and NIH.

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  1. Department of Pharmacology, Lineberger Comprehensive Cancer Center, and Center for Thrombosis and Hemostasis, University of North Carolina, Chapel Hill, 27599-7365, North Carolina, USA

    Patricia J. Keely, John K. Westwick, Ian P. Whitehead, Channing J. Der & Leslie V. Parise

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  1. Patricia J. Keely
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Correspondence to Patricia J. Keely.

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Keely, P., Westwick, J., Whitehead, I. et al. Cdc42 and Rac1 induce integrin-mediated cell motility and invasiveness through PI(3)K. Nature 390, 632–636 (1997). https://doi.org/10.1038/37656

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