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Rab-coupling protein coordinates recycling of 5β1 integrin and EGFR1 to promote cell migration in 3D microenvironments

¹ Beatson Institute for Cancer Research, Bearsden, Glasgow G61 1BD, Scotland, UK
² Department of Microbiology, University of Pennsylvania, Philadelphia, PA 19104
³ Molecular Cell Biology Laboratory, Biochemistry Department, Biosciences Institute, University College Cork, Cork, Republic of Ireland

Correspondence to Jim Norman: j.norman{at}beatson.gla.ac.uk

Here we show that blocking the adhesive function of vβ3 integrin with soluble RGD ligands, such as osteopontin or cilengitide, promoted association of Rab-coupling protein (RCP) with 5β1 integrin and drove RCP-dependent recycling of 5β1 to the plasma membrane and its mobilization to dynamic ruffling protrusions at the cell front. These RCP-driven changes in 5β1 trafficking led to acquisition of rapid/random movement on two-dimensional substrates and to a marked increase in fibronectin-dependent migration of tumor cells into three-dimensional matrices. Recycling of 5β1 integrin did not affect its regulation or ability to form adhesive bonds with substrate fibronectin. Instead, 5β1 controlled the association of EGFR1 with RCP to promote the coordinate recycling of these two receptors. This modified signaling downstream of EGFR1 to increase its autophosphorylation and activation of the proinvasive kinase PKB/Akt. We conclude that RCP provides a scaffold that promotes the physical association and coordinate trafficking of 5β1 and EGFR1 and that this drives migration of tumor cells into three-dimensional matrices.

Abbreviations used in this paper: FIP, family of interacting protein; FN, fibronectin; RBD, Rab11-binding domain; RCP, Rab-coupling protein; Rip11, Rab11-interacting protein; RTK, receptor tyrosine kinase; shRNA, short hairpin RNA; Tfn-R, transferrin receptor.

© 2008 Caswell et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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