Integrin α₆β₄ Cooperates with LPA Signaling to Stimulate Rac Through AKAP-Lbc-Mediated RhoA Activation

Authors

Kathleen L. O'Connor, University of KentuckyFollow
Min Chen, University of KentuckyFollow
L. Nicole Towers, University of Kentucky

Abstract

The α₆β₄ integrin promotes carcinoma invasion through its ability to promote directed migration and polarization of carcinoma cells. In this study, we explore how the α₆β₄ integrin cooperates with lysophosphatidic acid (LPA) to activate Rho and Rac small GTPases. Through the use of dominant negative Rho constructs, C3 exotransferase, and Rho kinase inhibitor, we find that Rho is critical for LPA-dependent chemotaxis and lamellae formation. However, utilization of specific Rho isoforms depends on integrin α₆β₄ expression status. Integrin α₆β₄-negative MDA-MB-435 cells utilize only RhoC for motility, whereas integrin α₆β₄-expressing cells utilize RhoC but additionally activate and utilize RhoA for LPA-dependent cell motility and lamellae formation. Notably, the activation of RhoA by cooperative LPA and integrin α₆β₄ signaling requires the Rho guanine nucleotide exchange factor AKAP-Lbc. We also determine that integrin α₆β₄ cannot activate Rac1 directly but promotes LPA-mediated Rac1 activation that is dependent on RhoA activity and de novo β₁ integrin ligation. Finally, we find that the regulation of Rac1 and RhoA in response to LPA is differentially regulated by phosphodiesterases, PKA, and phosphatidylinositol 3-kinase, thus supporting their spatially distinct compartmentalization. In summary, signaling from integrin α₆β₄ facilitates LPA-stimulated chemotaxis through preferential activation of RhoA, which, in turn, facilitates activation of Rac1.

Document Type

Article

Publication Date

2-1-2012

Notes/Citation Information

Published in American Journal of Physiology-Cell Physiology, v. 302, issue 3, p. C605-C614.

Copyright © 2012 the American Physiological Society

Digital Object Identifier (DOI)

https://doi.org/10.1152/ajpcell.00095.2011

Funding Information

This work was supported by the United States Army Medical Research and Materiel Command Grant DAMD17-98-1-8033 and the National Institutes of Health Grant R01-CA109136.

Repository Citation

O'Connor, Kathleen L.; Chen, Min; and Towers, L. Nicole, "Integrin α₆β₄ Cooperates with LPA Signaling to Stimulate Rac Through AKAP-Lbc-Mediated RhoA Activation" (2012). Markey Cancer Center Faculty Publications. 123.
https://uknowledge.uky.edu/markey_facpub/123