An integrin-α4-14-3-3ζ-paxillin ternary complex mediates localised Cdc42 activity and accelerates cell migration

N.O Deakin, M.D Bass, S Warwood, J Schoelermann, Z Mostafavi-Pour, D Knight, C Ballestrem, M.J Humphries

Research output: Contribution to journalArticle (Academic Journal)peer-review

42 Citations (Scopus)

Abstract

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.
Translated title of the contributionAn integrin-α4-14-3-3ζ-paxillin ternary complex mediates localised Cdc42 activity and accelerates cell migration
Original languageEnglish
Pages (from-to)1654 - 1664
Number of pages11
JournalJournal of Cell Science
Volume122
Issue number10
DOIs
Publication statusPublished - May 2009

Fingerprint Dive into the research topics of 'An integrin-α4-14-3-3ζ-paxillin ternary complex mediates localised Cdc42 activity and accelerates cell migration'. Together they form a unique fingerprint.

Cite this