Integrin (red) associates with Type I PKA (green).

A-kinase anchoring proteins (AKAPs) aid the docking of cAMP-dependent protein kinase (PKA) to specific cellular regions during various signalling processes. There are two types of PKA that each differ in their regulatory (PKA-RI and II) and catalytic (PKA-CI and II) subunit makeup. Different AKAPs are either specific for only type II PKA or exhibit dual specificity for both types of PKA. Type I PKA is enriched at the front of migrating cells, where it phosphorylates 4 integrins. Although this locally restricted phosphorylation provides spatial cues governing cell motility, the details of the 4 integrin–PKA interaction are still poorly understood. Mark Ginsberg and colleagues now report in Nature Cell Biology that the cytoplasmic domain of 4 integrin is a novel form of type I PKA-specific AKAP.

The authors showed that PKA-RI colocalises with 4 integrin in migrating fibroblast protrusions. The cytoplasmic domain of 4 integrin, but not of other integrins, specifically interacts with the PKA holoenzyme-containing subunit PKA-RI, but not with PKA-RII. Importantly, the PKA-RI–4 integrin interaction differs from other AKAPs as it requires the presence of both the catalytic and regulatory subunits of PKA. The kinase activity, on the other hand, was required for phosphorylation of but not for binding to 4 integrin.

The authors investigated whether the type I PKA–4 integrin interaction influenced 41 integrin-dependent migration. They targeted either type I or type II PKA to the mitochondrion by transfecting Chinese Hamster Ovary (CHO) cells with modified PKA-R subunits (mitoAKB-RI or mitoAKB–RII). Phospho-4 integrin was detected at the leading edge of CHO cells expressing only mitoAKB–RII, indicating that leading-edge phosphorylation of 4 integrins requires the presence of type I PKA at the plasma membrane. Furthermore, mitoAKB RI-expressing cells exhibited defects in 4 integrin-mediated migration.

The anchoring of type I PKA by 4 integrin establishes unique roles for type I PKA in 4-mediated cell functions. 4 integrins cluster with antigen receptors to inhibit T-cell function, and 4 integrin phosphorylation leads to a reduction in the activation of tyrosine kinases that promote cell proliferation. Based on the results of this study, the authors postulate that both events involve the presence of type I PKA. Apart from the effects on signalling events, this study reveals a novel role for type I PKA in cell migration – type I PKA is recruited to the leading edge of migrating cells by its interaction with 4 integrins. This partitioning of type I PKA activity provides new insight into the maintenance of polarity during cell migration.

Author: Mirko von Elstermann