The type III TGF-beta receptor betaglycan transmembrane-cytoplasmic domain fragment is stable after ectodomain cleavage and is a substrate of the intramembrane protease gamma-secretase.

摘要

The Type III TGF-beta receptor, betaglycan, is a widely expressed proteoglycan co-receptor for TGF-beta superfamily ligands. The full-length protein undergoes ectodomain cleavage with release of a soluble ectodomain fragment. The fate of the resulting transmembrane-cytoplasmic fragment, however, has never been explored. We demonstrate here that the transmembrane-cytoplasmic fragment is stable in transfected cells and in cell lines expressing endogenous betaglycan. Production of this fragment is inhibited by the ectodomain shedding inhibitor TAPI-2. Treatment of cells with inhibitors of the intramembrane protease gamma-secretase stabilizes this fragment, suggesting that it is a substrate of gamma-secretase. Expression of the transmembrane-cytoplasmic fragment as well as gamma-secretase inhibitor stabilization are independent of TGF-beta1 or -beta2 and are unaffected by mutation of the cytoplasmic domain serines that undergo phosphorylation. gamma-Secretase inhibition or the expression of a transmembrane-cytoplasmic fragment in HepG2 cells blunted TGF-beta2 signaling. Our findings thus suggest that the transmembrane-cytoplasmic fragment remaining after betaglycan ectodomain cleavage is stable and a substrate of gamma-secretase, which may have significant implications for the TGF-beta signaling response.