Phosphorylation of the {alpha}-chain in the integrin LFA-1 enables {beta}2-chain phosphorylation and {alpha}-actinin binding required for cell adhesion [Immunology] (Journal of Biological Chemistry)

The integrin leukocyte function-associated antigen-1 (LFA-1) plays a pivotal role in leukocyte adhesion and migration, but the mechanism(s) by which this integrin is regulated has remained incompletely understood. LFA-1 integrin activity requires phosphorylation of its ?2-chain and interactions of its cytoplasmic tail with various cellular proteins. The ?-chain is constitutively phosphorylated and necessary for cellular adhesion, but how the ?-chain regulates adhesion has remained enigmatic. We now show that substitution of the ?-chain phosphorylation site (S1140A) in T cells inhibits the phosphorylation of the functionally important Thr-758 in the ?2-chain, binding of ?-actinin and 14-3-3 protein, and expression of an integrin-activating epitope after treatment with the stromal cell-derived factor-1?. The presence of this substitution resulted in a loss of cell adhesion and directional cell migration. Moreover, LFA-1 activation through the T-cell receptor in cells expressing the S1140A LFA-1 variant resulted in less Thr-758 phosphorylation, ?-actinin and talin binding, and cell adhesion. The finding that the LFA-1 ?-chain regulates adhesion through the ?-chain via specific phosphorylation at Ser-1140 in the ?-chain has not been previously reported and emphasizes that both chains are involved in the regulation of LFA-1 integrin activity.