Ethan Lee
Faculty Member
Last active: 8/24/2020

Phosphorylation of XIAP at threonine 180 controls its activity in Wnt signaling.

Ng VH, Hang BI, Sawyer LM, Neitzel LR, Crispi EE, Rose KL, Popay TM, Zhong A, Lee LA, Tansey WP, Huppert S, Lee E
J Cell Sci. 2018 131 (10)

PMID: 29678905 · PMCID: PMC6031333 · DOI:10.1242/jcs.210575

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 β-catenin-TCF/Lef complexes. We now demonstrate that XIAP is phosphorylated by GSK3 at threonine 180, and that an alanine mutant (XIAP) exhibits decreased Wnt activity compared to wild-type XIAP in cultured human cells and in embryos. Although XIAP ubiquitylates TLE3 at wild-type levels , it exhibits a reduced capacity to ubiquitylate and bind TLE3 in human cells. XIAP 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.

© 2018. Published by The Company of Biologists Ltd.

MeSH Terms (15)

Amino Acid Motifs Animals Apoptosis Regulatory Proteins Cell Line Glycogen Synthase Kinase 3 Humans Intracellular Signaling Peptides and Proteins Mitochondrial Proteins Phosphorylation Protein Binding Threonine Wnt3A Protein Wnt Signaling Pathway X-Linked Inhibitor of Apoptosis Protein Xenopus

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