The α1 integrin cytoplasmic tail interacts with phosphoinositides and interferes with Akt activation

Integrin alpha 1 beta 1 is an adhesion receptor that binds to collagen and laminin. It regulates cell adhesion, cytoskeletal organization, and migration. The cytoplasmic tail of the alpha 1 subunit consists of 15 amino acids and contains six positively charged lysine residues. In this study, we present evidence that the alpha 1 integrin cytoplasmic tail (alpha 1CT) directly associates with phosphoinositides, preferentially with phosphatidylinositol 3,4,5-trisphosphate (PI (3,4,5)P3). Since the association was disrupted by calcium, magnesium and phosphate ions, this interaction appears to be in ionic nature. Here, the peptide-lipid interaction was driven by the conserved KIGFFKR motif. The exchange of both two potential phospholipid-binding lysines for glycines in the KIGFFKR motif increased alpha 1 beta 1 integrin-specific adhesion and F-actin cytoskeleton formation compared to cells expressing the unmodified alpha 1 subunit, whereas only mutation of the second lysine at position 1171 increased levels of constitutively active alpha 1 beta 1 integrins on the cell surface. In addition, enhanced focal adhesion formation and increased phosphorylation of focal adhesion kinase, but decreased phosphorylation of AKT was observed in these cells. We conclude that the KIGFFKR motif, and in particular lysine1171 is involved in the dynamic regulation of alpha 1 beta 1 integrin activity and that the interaction of alpha 1CT with phosphoinositides may contribute to this process.