A molecular mechanism of integrin crosstalk:: αvβ3 suppression of calcium/calmodulin-dependent protein kinase II regulates α5β1 function

Many cells express more than one integrin receptor for extracellular matrix, and in vivo these receptors map be simultaneously engaged. Ligation of one integrin may influence the behavior of others on the cell, a phenomenon we have called integrin crosstalk. Ligation of the integrin alpha(v)beta(3) inhibits both phagocytosis and migration mediated by alpha(5)beta(1) on the same cell, and the beta(3) cytoplasmic tail is necessary and sufficient for this regulation of alpha(5)beta(1) Ligation of alpha(5)beta(1) activates the calcium- and calmodulin-dependent protein kinase II (CamKII). This activation is required for alpha(5)beta(1)-mediated phagocytosis and migration. Simultaneous ligation of alpha(v)beta(3) or expression of a chimeric molecule with a free pg cytoplasmic tail prevents alpha(5)beta(1)-mediated activation of CamKII. Expression of a constitutively active CamKII restores alpha(5)beta(1) functions blocked by alpha(v)beta(3)-initiated integrin crosstalk. Thus. alpha(v)beta(3) inhibition of alpha(5)beta(1) activation of CamKII is required for its role in integrin crosstalk. Structure-function analysis of the beta 3 cytoplasmic tail demonstrates a requirement fur Ser752 in beta(3)-mediated suppression of CamKII activation, while crosstalk is independent of Tyr747 and Tyr759, implicating Ser752, but not beta(3) tyrosine phosphorylation in initiation of the alpha(v)beta(3) Signal for integrin crosstalk.