免疫亲和蛋白FKBP12作为转化生长因子β家族I型受体的常见抑制剂发挥作用。

The immunophilin FKBP12 functions as a common inhibitor of the TGF beta family type I receptors.

作者信息

Wang T, Li B Y, Danielson P D, Shah P C, Rockwell S, Lechleider R J, Martin J, Manganaro T, Donahoe P K

机构信息

Massachusetts General Hospital Department of Surgery Harvard Medical School Boston 02114, USA.

出版信息

Cell. 1996 Aug 9;86(3):435-44. doi: 10.1016/s0092-8674(00)80116-6.

DOI:10.1016/s0092-8674(00)80116-6

PMID:8756725

Abstract

The immunophilin FKBP12 is an evolutionarily conserved abundant protein; however, its physiological roles remain poorly defined. Here we report that FKBP12 is a common cytoplasmic interactor of TGF beta family type I receptors. FKBP12 binds to ligand-free TGF beta type I receptor, from which it is released upon a ligand-induced, type II receptor mediated phosphorylation of the type I receptor. Blocking FKBP12/type I receptor interaction with FK506 nonfunctional derivatives enhances the ligand activity, indicating that FKBP12 binding is inhibitory to the signaling pathways of the TGF beta family ligands. Overexpression of a myristylated FKBP12 in Mv1Lu cell specifically inhibits two separate pathways activated by TGF beta, and two point mutations on FKBP12 (G89P, I90K) abolish the inhibitory activity of FKBP12, suggesting that FKBP12 may dock a cytoplasmic protein to the type I receptors to inhibit TGF beta family mediated signaling.

摘要

免疫亲和蛋白FKBP12是一种在进化上保守的丰富蛋白质；然而，其生理作用仍不清楚。在此我们报告，FKBP12是转化生长因子β（TGFβ）家族I型受体常见的胞质相互作用蛋白。FKBP12与无配体的TGFβ I型受体结合，在配体诱导的、II型受体介导的I型受体磷酸化后从该受体上释放。用FK506无功能衍生物阻断FKBP12/I型受体相互作用可增强配体活性，表明FKBP12结合对TGFβ家族配体的信号通路具有抑制作用。在Mv1Lu细胞中过表达肉豆蔻酰化的FKBP12可特异性抑制由TGFβ激活的两条独立途径，FKBP12上的两个点突变（G89P、I90K）消除了FKBP12的抑制活性，提示FKBP12可能将一种胞质蛋白对接至I型受体以抑制TGFβ家族介导的信号传导。