Calcium and Calmodulin-dependent Serine/Threonine Protein Kinase Type II (CaMKII)-mediated Intramolecular Opening of Integrin Cytoplasmic Domain-associated Protein-1 (ICAP-1α) Negatively Regulates β1 Integrins

Focal adhesion turnover during cell migration is an integrated cyclic process requiring tight regulation of integrin function. Interaction of integrin with its ligand depends on its activation state, which is regulated by the direct recruitment of proteins onto the beta integrin chain cytoplasmic domain. We previously reported that ICAP-1 alpha, a specific cytoplasmic partner of beta 1A integrins, limits both talin and kindlin interaction with beta 1 integrin, thereby restraining focal adhesion assembly. Here we provide evidence that the calcium and calmodulin-dependent serine/threonine protein kinase type II (CaMKII) is an important regulator of ICAP-1 alpha for controlling focal adhesion dynamics. CaMKII directly phosphorylates ICAP-1 alpha and disrupts an intramolecular interaction between the N- and the C-terminal domains of ICAP-1 alpha, unmasking the PTB domain, thereby permitting ICAP-1 alpha binding onto the beta 1 integrin tail. ICAP-1 alpha direct interaction with the beta 1 integrin tail and the modulation of beta 1 integrin affinity state are required for down-regulating focal adhesion assembly. Our results point to a molecular mechanism for the phosphorylation-dependent control of ICAP-1 alpha function by CaMKII, allowing the dynamic control of beta 1 integrin activation and cell adhesion.