Cross Talk among TGF-β Signaling Pathways, Integrins, and the Extracellular Matrix

The growth factor TGF-beta is secreted in a latent complex consisting of three proteins: TGF-beta, an inhibitor (latency-associated protein, LAP, which is derived from the TGF-beta propeptide) and an ECM-binding protein (one of the latent TGF-beta binding proteins, or LTBPs). LTBPs interact with fibrillins and other ECM components and thus function to localize latent TGF-beta in the ECM. LAP contains an integrin-binding site (RGD), and several RGD-binding integrins are able to activate latent TGF-beta through binding this site. Mutant mice defective in integrin-mediated activators, and humans and mice with fibrillin gene mutations, show the critical role of ECM and integrins in regulating TGF-beta signaling.