Abstract:
:Alpha4 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 alpha4 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 alpha4 integrin cytoplasmic domain with 14-3-3zeta. This interaction depends on serine phosphorylation of alpha4 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 alpha4 integrin and 14-3-3zeta is enhanced by the direct association between 14-3-3zeta and paxillin, resulting in the formation of a ternary complex that stabilises the recruitment of each component. Although pair-wise interaction between alpha4 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 alpha4 integrin-dependent migration.
journal_name
J Cell Scijournal_title
Journal of cell scienceauthors
Deakin NO,Bass MD,Warwood S,Schoelermann J,Mostafavi-Pour Z,Knight D,Ballestrem C,Humphries MJdoi
10.1242/jcs.049130subject
Has Abstractpub_date
2009-05-15 00:00:00pages
1654-64issue
Pt 10eissn
0021-9533issn
1477-9137pii
jcs.049130journal_volume
122pub_type
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