The type III TGF-β receptor betaglycan transmembrane-cytoplasmic domain fragment is stable after ectodomain cleavage and is a substrate of the intramembrane protease γ-secretase
The type III TGF-β receptor betaglycan transmembrane-cytoplasmic domain fragment is stable after ectodomain cleavage and is a substrate of the intramembrane protease γ-secretase
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DOI：
10.1016/j.bbamcr.2010.12.005
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发表时间：
2011-02-01
影响因子：
5.1
通讯作者：
Wells, Rebecca G.
中科院分区：
文献类型：
--
作者：
Blair, Cheyne R.;Stone, Jacqueline B.;Wells, Rebecca G.
III型TGF-β受体β聚糖是TGF-β超家族配体的广泛表达的蛋白聚糖共受体。全长蛋白质经历胞外域切割，释放可溶性胞外域片段。然而，所产生的跨膜-胞质片段的命运从未被探索过。我们在此证明，跨膜-胞质片段在转染细胞和表达内源性β聚糖的细胞系中是稳定的。该片段的产生受到胞外域脱落抑制剂TAPI-2的抑制。用膜内蛋白酶γ-分泌酶的抑制剂处理细胞可以稳定该片段，表明它是γ-分泌酶的底物。跨膜-胞质片段的表达以及γ-分泌酶抑制剂的稳定性与TGF-β 1或TGF-β 2无关，并且不受经历磷酸化的胞质结构域丝氨酸突变的影响。γ-分泌酶抑制或HepG 2细胞中跨膜-胞质片段的表达减弱了TGF-β 2信号传导。因此，我们的研究结果表明，transmembran-cytoplasmic片段剩余后β聚糖胞外域切割是稳定的，γ-分泌酶的底物，这可能有显着的影响TGF-β信号转导反应。(C)2010 Elsevier B. V.保留所有权利。
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-beta 1 or -beta 2 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-beta 2 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. (C) 2010 Elsevier B.V. All rights reserved.