The Type II Transforming Growth Factor (TGF)-b Receptor-interacting Protein TRIP-1 Acts as a Modulator of the TGF-b Response*

The transforming growth factor-b (TGF-b) receptor interacting protein TRIP-1 was originally identified as a WD40 repeat-containing protein that has the ability to associate with the TGF-b 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-b to induce transcription from the plasminogen activator inhibitor-1 promoter, a common reporter of the TGF-b-induced gene expression response, but does not affect the ability of TGF-b to inhibit cyclin A transcription. TRIP-1 can also inhibit the plasminogen activator inhibitor-1 expression induced by Smads as well as activated TGF-b type I receptors. Its inhibitory effect is exerted by a combination of receptordependent 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-b-induced gene expression response and therefore may exert a dominant negative phenotype. We conclude that TRIP-1 acts as a modulator of the TGF-b response.