The β3 integrin cytoplasmic tail: protein scaffold and control freak

Platelet integrin alpha IIb beta 3 plays an essential role in thrombus formation through interactions with adhesive ligands. Successful parenteral blockade of these interactions has validated alpha IIb beta 3 as a therapeutic target in cardiovascular medicine. However, oral aIIbb3 antagonists have not been successful and there is an unmet need for more effective antiplatelet drugs. Growing evidence points to the cytoplasmic tails of alpha IIb and beta 3, and the beta 3 tail in particular, as scaffolds for intracellular proteins that mediate inside-out signaling and regulate alpha IIb beta 3 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 beta 3 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.