Tyrosine phosphorylation of integrin beta3 regulates kindlin-2 binding and integrin activation.
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Bledzka K, Bialkowska K, Nie H, Qin J, Byzova T, Wu C, Plow EF, Ma YQ
Tyrosine phosphorylation of integrin beta3 regulates kindlin-2 binding and integrin activation.
J Biol Chem. 2010 Oct 1;285(40):30370-4. doi: 10.1074/jbc.C110.134247. Epub 2010 Aug 11.
- PubMed ID
- 20702409 [ View in PubMed]
- Abstract
Kindlins are essential for integrin activation in cell systems and do so by working in a cooperative fashion with talin via their direct interaction with integrin beta cytoplasmic tails (CTs). Kindlins interact with the membrane-distal NxxY motif, which is distinct from the talin-binding site within the membrane-proximal NxxY motif. The Tyr residues in both motifs can be phosphorylated, and it has been suggested that this modification of the membrane-proximal NxxY motif negatively regulates interaction with the talin head domain. However, the influence of Tyr phosphorylation of the membrane-distal NxxY motif on kindlin binding is unknown. Using mutational analyses and phosphorylated peptides, we show that phosphorylation of the membrane-distal NITY(759) motif in the beta(3) CT disrupts kindlin-2 recognition. Phosphorylation of this membrane-distal Tyr also disables the ability of kindlin-2 to coactivate the integrin. In direct binding studies, peptides corresponding to the non-phosphorylated beta(3) CT interacted well with kindlin-2, whereas the Tyr(759)-phosphorylated peptide failed to bind kindlin-2 with measurable affinity. These observations indicate that transitions between the phosphorylated and non-phosphorylated states of the integrin beta(3) CT determine reactivity with kindlin-2 and govern the role of kindlin-2 in regulating integrin activation.