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Active Rho is localized to podosomes induced by oncogenic Src and is required for their assembly and function

Cancer Research Laboratory, and Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA 94720

Address correspondence to G. Steven Martin, Dept. of Molecular and Cell Biology, 16 Barker Hall, #3204, University of California at Berkeley, Berkeley, CA 94720-3204. Tel.: (510) 642-1508. Fax: (510) 643-1729. email: smartin{at}socrates.berkeley.edu

Abstract

Transformation of fibroblasts by oncogenic Src causes disruption of actin stress fibers and formation of invasive adhesions called podosomes. Because the small GTPase Rho stimulates stress fiber formation, Rho inactivation by Src has been thought to be necessary for stress fiber disruption. However, we show here that Rho[GTP] levels do not decrease after transformation by activated Src. Inactivation of Rho in Src-transformed fibroblasts by dominant negative RhoA or the Rho-specific inhibitor C3 exoenzyme disrupted podosome structure as judged by localization of podosome components F-actin, cortactin, and Fish. Inhibition of Rho strongly inhibited Src-induced proteolytic degradation of the extracellular matrix. Furthermore, development of an in situ Rho[GTP] affinity assay allowed us to detect endogenous Rho[GTP] at podosomes, where it colocalized with F-actin, cortactin, and Fish. Therefore, Rho is not globally inactivated in Src-transformed fibroblasts, but is necessary for the assembly and function of structures implicated in tumor cell invasion.

Key Words: oncogene protein pp60(v-src); neoplastic cell transformation; rho GTP-binding proteins; cell membrane protrusions; signal transduction

L. Kim's present address is ALZA Corporation, 1058B Huff Ave., Mountain View, CA 94043.

Abbreviations used in this paper: RBD, Rho binding domain; ts-v-Src, temperature-sensitive v-Src.

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