Su YunYun, Fu Chunjiang, Ishikawa Shinji, Stella Alessandra, Kojima Masayuki, Shitoh Kazuhisa, Schreiber Emanuel M, Day Billy W, Liu Bo
Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Mol Cell. 2008 Dec 5;32(5):652-61. doi: 10.1016/j.molcel.2008.10.023.
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.
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。
