The beta3 integrin cytoplasmic tail: protein scaffold and control freak.

Platelet integrin alphaIIbbeta3 plays an essential role in thrombus formation through interactions with adhesive ligands. Successful parenteral blockade of these interactions has validated alphaIIbbeta3 as a therapeutic target in cardiovascular medicine. However, oral alphaIIbbeta3 antagonists have not been successful and there is an unmet need for more effective anti-platelet drugs. Growing evidence points to the cytoplasmic tails of alphaIIb and beta3, and the beta3 tail in particular, as scaffolds for intracellular proteins that mediate inside-out signaling and regulate alphaIIbbeta3 affinity for ligands. Intracellular protein interactions with the integrin cytoplasmic tails also regulate outside-in signals to the actin cytoskeleton. Here we focus on recent studies that illustrate the relevance of the beta3 cytoplasmic tail as a regulatory scaffold in vivo. We speculate that this scaffold or its interacting proteins may serve as therapeutic targets for the development of future anti-thrombotic drugs.