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First published online 28 April 2009
doi: 10.1242/jcs.049130

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An integrin-4–14-3-3–paxillin ternary complex mediates localised Cdc42 activity and accelerates cell migration

Nicholas O. Deakin^1,*,, Mark D. Bass^1,*, Stacey Warwood¹, Julia Schoelermann^2,3, Zohreh Mostafavi-Pour^1,, David Knight¹, Christoph Ballestrem¹ and Martin J. Humphries^1,¶

¹ Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, UK
² Department of New Materials and Biosystems, Max-Planck-Institute for Metals Research, Heisenbergstrasse 3, D-70569, Germany
³ Department of Biophysical Chemistry, University of Heidelberg, INF 235, 69120 Heidelberg, Germany

^¶ Author for correspondence (e-mail: martin.humphries{at}manchester.ac.uk)

Accepted 5 February 2009

4 integrins are used by leukocytes and neural crest derivatives for adhesion and migration during embryogenesis, immune responses and tumour invasion. The pro-migratory activity of 4 integrin is mediated in part through the direct binding of the cytoplasmic domain to paxillin. Here, using intermolecular FRET and biochemical analyses, we report a novel interaction of the 4 integrin cytoplasmic domain with 14-3-3. This interaction depends on serine phosphorylation of 4 integrin at a site (S978) distinct from that which regulates paxillin binding (S988). Using a combination of metabolic labelling and targeted mass spectrometry by multiple reaction monitoring we demonstrate the low stoichiometry phosphorylation of S978. The interaction between 4 integrin and 14-3-3 is enhanced by the direct association between 14-3-3 and paxillin, resulting in the formation of a ternary complex that stabilises the recruitment of each component. Although pair-wise interaction between 4 integrin and paxillin is sufficient for normal Rac1 regulation, the integrity of the ternary complex is essential for focused Cdc42 activity at the lamellipodial leading edge and directed cell movement. Taken together, these data identify a key signalling nexus mediating 4 integrin-dependent migration.

Key words: Integrin, 14-3-3, Paxillin, Cdc42, Migration

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