Abstract
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 β integrin chain cytoplasmic domain. We previously reported that ICAP-1α, a specific cytoplasmic partner of β1A integrins, limits both talin and kindlin interaction with β1 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-1α for controlling focal adhesion dynamics. CaMKII directly phosphorylates ICAP-1α and disrupts an intramolecular interaction between the N- and the C-terminal domains of ICAP-1α, unmasking the PTB domain, thereby permitting ICAP-1α binding onto the β1 integrin tail. ICAP-1α direct interaction with the β1 integrin tail and the modulation of β1 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-1α function by CaMKII, allowing the dynamic control of β1 integrin activation and cell adhesion.
Highlights
Integrin affinity is controlled by the recruitment of both activators and inactivators on their cytoplasmic domain
On a VN matrix or in Icap-1 null background, ␣CaMKIIT286D did not mediate any deleterious effect on focal adhesion (FA) growth, suggesting that calmodulin-dependent serine/threonine protein kinase type II (CaMKII) acts on 1 integrin-specific adhesion sites through ICAP-1␣ (Fig. 1, a and c)
We showed that ICAP-1␣ phosphorylation by CaMKII enabled its interaction with the 1A integrin cytosolic tail by allowing the accessibility to the PTB domain and thereby regulating FA dynamics (Fig. 7)
Summary
Integrin affinity is controlled by the recruitment of both activators and inactivators on their cytoplasmic domain. Interaction of integrin with its ligand depends on its activation state, which is regulated by the direct recruitment of proteins onto the  integrin chain cytoplasmic domain. The substrate of CaMKII was not clearly identified from those studies, we previously reported that CaMKII inhibition could be overcome by ectopically expressing a mutant form of ICAP-1␣ in which the threonine 38 of the CaMKII consensus site has been substituted by a non-phosphorylatable alanine [27] This finding suggested that both proteins were involved in the same signaling pathway. To test this hypothesis, we used a combination of 1 integrin and ICAP-1␣ mutants and showed that CaMKII controls the capability of ICAP-1␣ to bind to 1 integrin and regulate focal adhesion dynamics. The resulting opened active form of ICAP-1␣ interacted with the 1A integrin tail and negatively regulated 1 integrin function by slowing down FA turnover
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