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

Integrin α₁β₁ is an adhesion receptor that binds to collagen and laminin. It regulates cell adhesion, cytoskeletal organization, and migration. The cytoplasmic tail of the α₁ subunit consists of 15 amino acids and contains six positively charged lysine residues. In this study, we present evidence that the α₁ integrin cytoplasmic tail (α₁CT) 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 α₁β₁ integrin-specific adhesion and F-actin cytoskeleton formation compared to cells expressing the unmodified α₁ subunit, whereas only mutation of the second lysine at position 1171 increased levels of constitutively active α₁β₁ 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 α₁β₁ integrin activity and that the interaction of α₁CT with phosphoinositides may contribute to this process.