RCP-driven 5 1 recycling suppresses Rac and promotes RhoA activity via the RacGAP1-IQGAP1 complex

Jacquemet, G., Green, D.M., Bridgewater, R.E., von Kriegsheim, A., Humphries, M.J., Norman, J.C. and Caswell, P.T. (2013) RCP-driven 5 1 recycling suppresses Rac and promotes RhoA activity via the RacGAP1-IQGAP1 complex. Journal of Cell Biology, 202(6), pp. 917-935. (doi: 10.1083/jcb.201302041)

Abstract

Inhibition of αvβ3 or expression of mutant p53 promotes invasion into fibronectin (FN)-containing extracellular matrix (ECM) by enhancing Rab-coupling protein (RCP)–dependent recycling of α5β1 integrin. RCP and α5β1 cooperatively recruit receptor tyrosine kinases, including EGFR1, to regulate their trafficking and downstream signaling via protein kinase B (PKB)/Akt, which, in turn, promotes invasive migration. In this paper, we identify a novel PKB/Akt substrate, RacGAP1, which is phosphorylated as a consequence of RCP-dependent α5β1 trafficking. Phosphorylation of RacGAP1 promotes its recruitment to IQGAP1 at the tips of invasive pseudopods, and RacGAP1 then locally suppresses the activity of the cytoskeletal regulator Rac and promotes the activity of RhoA in this subcellular region. This Rac to RhoA switch promotes the extension of pseudopodial processes and invasive migration into FN-containing matrices, in a RhoA-dependent manner. Thus, the localized endocytic trafficking of α5β1 within the tips of invasive pseudopods elicits signals that promote the reorganization of the actin cytoskeleton, protrusion, and invasion into FN-rich ECM.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Norman, Professor James
• Authors: Jacquemet, G., Green, D.M., Bridgewater, R.E., von Kriegsheim, A., Humphries, M.J., Norman, J.C., and Caswell, P.T.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Journal of Cell Biology
• Publisher: Rockefeller University Press
• ISSN: 0021-9525
• ISSN (Online): 1540-8140
• Copyright Holders: Copyright © 2013 The Authors
• First Published: First published in the Journal of Cell Biology 202(6):917-935
• Publisher Policy: Reproduced under a Creative Commons License