GARP regulates the bioavailability and activation of TGFbeta.
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Wang R, Zhu J, Dong X, Shi M, Lu C, Springer TA
GARP regulates the bioavailability and activation of TGFbeta.
Mol Biol Cell. 2012 Mar;23(6):1129-39. doi: 10.1091/mbc.E11-12-1018. Epub 2012 Jan 25.
- PubMed ID
- 22278742 [ View in PubMed]
- Abstract
Glycoprotein-A repetitions predominant protein (GARP) associates with latent transforming growth factor-beta (proTGFbeta) on the surface of T regulatory cells and platelets; however, whether GARP functions in latent TGFbeta activation and the structural basis of coassociation remain unknown. We find that Cys-192 and Cys-331 of GARP disulfide link to the TGFbeta1 prodomain and that GARP with C192A and C331A mutations can also noncovalently associate with proTGFbeta1. Noncovalent association is sufficiently strong for GARP to outcompete latent TGFbeta-binding protein for binding to proTGFbeta1. Association between GARP and proTGFbeta1 prevents the secretion of TGFbeta1. Integrin alpha(V)beta(6) and to a lesser extent alpha(V)beta(8) are able to activate TGFbeta from the GARP-proTGFbeta1 complex. Activation requires the RGD motif of latent TGFbeta, disulfide linkage between GARP and latent TGFbeta, and membrane association of GARP. Our results show that GARP is a latent TGFbeta-binding protein that functions in regulating the bioavailability and activation of TGFbeta.