A Molecular Mechanism of Integrin Crosstalk: α(v)β(3 )Suppression of Calcium/Calmodulin-dependent Protein Kinase II Regulates α(5)β(1) 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(v)β(3) inhibits both phagocytosis and migration mediated by α(5)β(1) on the same cell, and the β(3) cytoplasmic tail is necessary and sufficient for this regulation of α(5)β(1). Ligation of α(5)β(1) activates the calcium- and calmodulin-dependent protein kinase II (CamKII). This activation is required for α(5)β(1)-mediated phagocytosis and migration. Simultaneous ligation of α(v)β(3) or expression of a chimeric molecule with a free β(3) cytoplasmic tail prevents α(5)β(1)-mediated activation of CamKII. Expression of a constitutively active CamKII restores α(5)β(1) functions blocked by α(v)β(3)-initiated integrin crosstalk. Thus, α(v)β(3) inhibition of α(5)β(1) activation of CamKII is required for its role in integrin crosstalk. Structure-function analysis of the β(3) cytoplasmic tail demonstrates a requirement for Ser752 in β(3)-mediated suppression of CamKII activation, while crosstalk is independent of Tyr747 and Tyr759, implicating Ser752, but not β(3) tyrosine phosphorylation in initiation of the α(v)β(3) signal for integrin crosstalk.