Integrin-specific signaling pathways controlling focal adhesion formation and cell migration

doi:10.1083/jcb.200210176

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Published 14 April 2003. doi:10.1083/jcb.200210176

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© The Rockefeller University Press, 0021-9525/2003/4/155 $5.00
The Journal of Cell Biology, Volume 161, Number 1, 155-167

Article

Integrin-specific signaling pathways controlling focal adhesion formation and cell migration

Zohreh Mostafavi-Pour¹, Janet A. Askari¹, Scott J. Parkinson², Peter J. Parker², Tony T.C. Ng³^,4 and Martin J. Humphries¹

¹ Wellcome Trust Centre for Cell Matrix Research, School of Biological Sciences, University of Manchester, Manchester M13 9PT, UK
² Protein Phosphorylation Laboratory, Cancer Research UK Laboratories, London WC2A 3PX, UK
³ Randall Centre, New Hunt's House, Guy's Medical School Campus, King's College London, London SE1 1UL, UK
⁴ Richard Dimbleby/Cancer Research UK Department of Cancer Research, St. Thomas' Hospital, London SE1 7EH, UK

Address correspondence to Martin J. Humphries, School of Biological Sciences, University of Manchester, 2.205 Stopford Building, Oxford Rd., Manchester M13 9PT, UK. Tel.: 44 (0) 161-275-5071. Fax: 44 (0) 161-275-1505. E-mail: martin.humphries{at}man.ac.uk

The fibronectin (FN)-binding integrins ${alpha}$ 4ß1 and ${alpha}$ 5ß1confer different cell adhesive properties, particularly withrespect to focal adhesion formation and migration. After analysesof ${alpha}$ 4⁺/ ${alpha}$ 5⁺ A375-SM melanoma cell adhesion to fragments of FN thatinteract selectively with ${alpha}$ 4ß1 and ${alpha}$ 5ß1, wenow report two differences in the signals transduced by eachreceptor that underpin their specific adhesive properties. First, ${alpha}$ 5ß1 and ${alpha}$ 4ß1 have a differential requirementfor cell surface proteoglycan engagement for focal adhesionformation and migration; ${alpha}$ 5ß1 requires a proteoglycancoreceptor (syndecan-4), and ${alpha}$ 4ß1 does not. Second,adhesion via ${alpha}$ 5ß1 caused an eightfold increase in proteinkinase C ${alpha}$ (PKC ${alpha}$ ) activation, but only basal PKC ${alpha}$ activity was observedafter adhesion via ${alpha}$ 4ß1. Pharmacological inhibitionof PKC ${alpha}$ and transient expression of dominant-negative PKC ${alpha}$ , butnot dominant-negative PKC ${delta}$ or PKC ${zeta}$ constructs, suppressed focaladhesion formation and cell migration mediated by ${alpha}$ 5ß1,but had no effect on ${alpha}$ 4ß1. These findings demonstratethat different integrins can signal to induce focal adhesionformation and migration by different mechanisms, and they identifyPKC ${alpha}$ signaling as central to the functional differences between ${alpha}$ 4ß1 and ${alpha}$ 5ß1.

Key Words: fibronectin; syndecan; PKC; cytoskeleton; vinculin

The online version of this article includes supplemental material.

^* Abbreviations used in this paper: BIM, bisindolylmaleimide;CCBD, central cell–binding domain; FN, fibronectin; HBD,heparin-binding domain; HepII, COOH-terminal heparin bindingdomain of fibronectin; IIICS, type III connecting segment; PIP2,phosphatidylinositol-4,5-bisphosphate.

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