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XB-ART-45567
Cell. June 22, 2012; 149 (7): 1565-77.

Tiki1 is required for head formation via Wnt cleavage-oxidation and inactivation.

Zhang X , Abreu JG , Yokota C , MacDonald BT , Singh S , Coburn KL , Cheong SM , Zhang MM , Ye QZ , Hang HC , Steen H , He X .


Abstract
Secreted Wnt morphogens are signaling molecules essential for embryogenesis, pathogenesis, and regeneration and require distinct modifications for secretion, gradient formation, and activity. Whether Wnt proteins can be posttranslationally inactivated during development and homeostasis is unknown. Here we identify, through functional cDNA screening, a transmembrane protein Tiki1 that is expressed specifically in the dorsal Spemann-Mangold Organizer and is required for anterior development during Xenopus embryogenesis. Tiki1 antagonizes Wnt function in embryos and human cells via a TIKI homology domain that is conserved from bacteria to mammals and acts likely as a protease to cleave eight amino-terminal residues of a Wnt protein, resulting in oxidized Wnt oligomers that exhibit normal secretion but minimized receptor-binding capability. Our findings identify a Wnt-specific protease that controls head formation, reveal a mechanism for morphogen inactivation through proteolysis-induced oxidation-oligomerization, and suggest a role of the Wnt amino terminus in evasion of oxidizing inactivation. TIKI proteins may represent potential therapeutic targets.

PubMed ID: 22726442
PMC ID: PMC3383638
Article link: Cell.
Grant support: GM057603S1 NIGMS NIH HHS , P30 HD-18655 NICHD NIH HHS , R01 GM057603 NIGMS NIH HHS , R01 GM087544-01 NIGMS NIH HHS , R01-GM094844-01 NIGMS NIH HHS , R01 GM087544 NIGMS NIH HHS , R01 GM094844 NIGMS NIH HHS , P30 HD-18655 NICHD NIH HHS , R01 GM057603 NIGMS NIH HHS , R01 GM094844 NIGMS NIH HHS , GM057603S1 NIGMS NIH HHS , R01 GM087544 NIGMS NIH HHS , P30 HD018655 NICHD NIH HHS , R01-GM094844-01 NIGMS NIH HHS , R01 GM087544-01 NIGMS NIH HHS

Genes referenced: clstn2 diexf dkk1 dvl1 dvl2 en2 foxg1 gsc ldlr lrp6 nodal nodal1 nodal3.1 otx2 rspo1 trabd2a trabd2b wnt11b wnt3a wnt5a wnt8a

Morpholinos referenced: trabd2 MO1

References:
Brannon, 1997, Pubmed, Xenbase[+]


Article Images: [+] show captions

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