FKBP12 is a negative regulator of transforming growth factor-beta receptorinternalization

Transforming growth factor-beta (TGF-beta) family polypeptides regulate cel l growth and differentiation by binding to single pass serine/threonine kin ases referred to as TGF-beta type I and II receptors. Although interaction screens have shown that the immunophilin FKBP12 interacts with TGF-beta typ e I receptors, the role of FKBP12 in TGF-beta receptor action is presently unclear. Using a chimeric TGF-beta receptor system, we have shown a specifi c enhancement of internalization when FKBP12 binding to the type I receptor was prevented with rapamycin. Moreover, although earlier studies demonstra ted that type II receptor kinase activity was required for optimal internal ization in mesenchymal cells, we found that rapamycin functioned downstream of the type II receptor kinase. Thus, rather than modulating TGF-beta sign aling, our data suggest a novel role for FKBP12 as a negative regulator of TGF-beta receptor endocytosis.