A Molecular Mechanism of Integrin Crosstalk: α_vβ₃ 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 may 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 α_vβ₃ inhibits both phagocytosis and migration mediated by α₅β₁ on the same cell, and the β₃ cytoplasmic tail is necessary and sufficient for this regulation of α₅β₁. Ligation of α₅β₁ activates the calcium- and calmodulin-dependent protein kinase II (CamKII). This activation is required for α₅β₁-mediated phagocytosis and migration. Simultaneous ligation of α_vβ₃ or expression of a chimeric molecule with a free β₃ cytoplasmic tail prevents α₅β₁-mediated activation of CamKII. Expression of a constitutively active CamKII restores α₅β₁ functions blocked by α_vβ₃-initiated integrin crosstalk. Thus, α_vβ₃ inhibition of α₅β₁ activation of CamKII is required for its role in integrin crosstalk. Structure-function analysis of the β₃ cytoplasmic tail demonstrates a requirement for Ser752 in β₃-mediated suppression of CamKII activation, while crosstalk is independent of Tyr747 and Tyr759, implicating Ser752, but not β₃ tyrosine phosphorylation in initiation of the α_vβ₃ signal for integrin crosstalk.