APC对于将磷酸化的β-连环蛋白靶向至SCFβ-TrCP泛素连接酶至关重要。

APC is essential for targeting phosphorylated beta-catenin to the SCFbeta-TrCP ubiquitin ligase.

作者信息

Su YunYun, Fu Chunjiang, Ishikawa Shinji, Stella Alessandra, Kojima Masayuki, Shitoh Kazuhisa, Schreiber Emanuel M, Day Billy W, Liu Bo

机构信息

Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, USA.

出版信息

Mol Cell. 2008 Dec 5;32(5):652-61. doi: 10.1016/j.molcel.2008.10.023.

DOI:10.1016/j.molcel.2008.10.023

PMID:19061640

Abstract

Ubiquitin-dependent proteolysis is an important mechanism that suppresses the beta-catenin transcription factor in cells without Wnt stimulation. A critical step in this regulatory pathway is to create a SCF(beta-TrCP) E3 ubiquitin ligase binding site for beta-catenin. Here we show that the SCF(beta-TrCP) binding site created by phosphorylation of beta-catenin is highly vulnerable to protein phosphatase 2A (PP2A) and must be protected by the adenomatous polyposis coli (APC) tumor suppressor protein. Specifically, phosphorylated beta-catenin associated with the wild-type APC protein is recruited to the SCF(beta-TrCP) complex, ubiquitin conjugated, and degraded. A mutation in APC that deprives this protective function exposes the N-terminal phosphorylated serine/threonine residues of beta-catenin to PP2A. Dephosphorylation at these residues by PP2A eliminates the SCF(beta-TrCP) recognition site and blocks beta-catenin ubiquitin conjugation. Thus, by acting to protect the E3 ligase binding site, APC ensures the ubiquitin conjugation of phosphorylated beta-catenin.

摘要

泛素依赖性蛋白水解是一种重要机制，可在没有Wnt刺激的细胞中抑制β-连环蛋白转录因子。该调节途径中的关键步骤是为β-连环蛋白创建一个SCF（β-TrCP）E3泛素连接酶结合位点。在此我们表明，由β-连环蛋白磷酸化产生的SCF（β-TrCP）结合位点极易受到蛋白磷酸酶2A（PP2A）的影响，并且必须由腺瘤性息肉病大肠杆菌（APC）肿瘤抑制蛋白进行保护。具体而言，与野生型APC蛋白相关的磷酸化β-连环蛋白被招募到SCF（β-TrCP）复合物中，进行泛素偶联并降解。APC中的一个丧失这种保护功能的突变会使β-连环蛋白的N端磷酸化丝氨酸/苏氨酸残基暴露于PP2A。PP2A对这些残基的去磷酸化消除了SCF（β-TrCP）识别位点并阻断了β-连环蛋白的泛素偶联。因此，通过保护E3连接酶结合位点，APC确保了磷酸化β-连环蛋白的泛素偶联。