Phosphorylation of XIAP at threonine 180 controls its activity in Wnt signaling
Phosphorylation of XIAP at threonine 180 controls its activity in Wnt signaling
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DOI：
10.1242/jcs.210575
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发表时间：
2018-05-15
影响因子：
4
通讯作者：
Lee, Ethan
中科院分区：
文献类型：
--
作者：
Ng, Victoria H.;Hang, Brian I.;Lee, Ethan
X-linked inhibitor of apoptosis （XIAP）在防止凋亡细胞死亡中起重要作用。XIAP已被证明参与信号通路，包括Wnt信号通路。XIAP通过促进协同抑制因子Groucho/TLE家族蛋白的单泛素化，降低其对TCF/Lef家族转录因子的亲和力，并允许转录活性β -catenin-TCF/Lef复合物的组装来调节Wnt信号。我们现在证明，在培养的人类细胞和爪蟾胚胎中，XIAP在苏氨酸180处被GSK3磷酸化，并且与野生型XIAP相比，丙氨酸突变体（XIAPT(180A)）的Wnt活性降低。尽管XIAPT（180A）在体外以野生型水平泛素化TLE3，但它在人细胞中泛素化和结合TLE3的能力降低。XIAPT（180A）结合Smac（也称为DIABLO），抑制fas诱导的细胞凋亡的程度与野生型XIAP相似。我们的研究揭示了一种新的机制，通过这种机制，XIAP专门针对Wnt信号功能而不是其抗凋亡功能。这些发现对人类癌症抗xiap疗法的开发具有启示意义。
X-linked inhibitor of apoptosis (XIAP) plays an important role in preventing apoptotic cell death. XIAP has been shown to participate in signaling pathways, including Wnt signaling. XIAP regulates Wnt signaling by promoting the monoubiquitylation of the co-repressor Groucho/TLE family proteins, decreasing its affinity for the TCF/Lef family of transcription factors and allowing assembly of transcriptionally active beta-catenin-TCF/Lef complexes. We now demonstrate that XIAP is phosphorylated by GSK3 at threonine 180, and that an alanine mutant (XIAPT(180A)) exhibits decreased Wnt activity compared to wild-type XIAP in cultured human cells and in Xenopus embryos. Although XIAPT(180A) ubiquitylates TLE3 at wildtype levels in vitro, it exhibits a reduced capacity to ubiquitylate and bind TLE3 in human cells. XIAPT(180A) binds Smac (also known as DIABLO) and inhibits Fas-induced apoptosis to a similar degree to wild-type XIAP. Our studies uncover a new mechanism by which XIAP is specifically directed towards a Wnt signaling function versus its anti-apoptotic function. These findings have implications for development of anti-XIAP therapeutics for human cancers.