The type II transforming growth factor (TGF)-β receptor-interacting protein TRIP-1 acts as a modulator of the TGF-β response

Abstract

The transforming growth factor-β (TGF-β) receptor interacting protein TRIP-1 was originally identified as a WD40 repeat-containing protein that has the ability to associate with the TGF-β type II receptor and is phosphorylated by it (1). However, its function was not known. We now show that TRIP-1 expression represses the ability of TGF-β to induce transcription from the plasminogen activator inhibitor-1 promoter, a common reporter of the TGF-β-induced gene expression response, but does not affect the ability of TGF-β to inhibit cyclin A transcription. TRIP-1 can also inhibit the plasminogen activator inhibitor-1 expression induced by Smads as well as activated TGF-β type I receptors. Its inhibitory effect is exerted by a combination of receptor-dependent and receptor-independent mechanisms. Deletion mutational analysis revealed that two distinct regions, which do not contain recognizable WD40 repeats, are required for the ability of TRIP-1 to inhibit the gene expression response. Expression of other segments of TRIP-1 increased the TGF-β-induced gene expression response and therefore may exert a dominant negative phenotype. We conclude that TRIP-1 acts as a modulator of the TGF-β response.