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

Xinjun Zhang, Jose Garcia Abreu, Chika Yokota, Bryan T. MacDonald, Sasha Singh, Karla Loureiro Almeida Coburn, Seong Moon Cheong, Mingzi M. Zhang, Qizhuang Ye, Howard C. Hang, Hanno Steen, Xi He

Research output: Contribution to journalArticle

63 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1565-1577
Number of pages13
JournalCell
Volume149
Issue number7
DOIs
StatePublished - Jun 22 2012

Fingerprint

Wnt Proteins
Embryonic Development
Peptide Hydrolases
Embryonic Organizers
Head
Proteolysis
Oxidation
Oligomerization
Mammals
Xenopus
Oligomers
Regeneration
Bacteria
Screening
Proteins
Homeostasis
Embryonic Structures
Complementary DNA
Cells
Molecules

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Zhang, X., Abreu, J. G., Yokota, C., MacDonald, B. T., Singh, S., Coburn, K. L. A., ... He, X. (2012). Tiki1 is required for head formation via wnt cleavage-oxidation and inactivation. Cell, 149(7), 1565-1577. https://doi.org/10.1016/j.cell.2012.04.039

Tiki1 is required for head formation via wnt cleavage-oxidation and inactivation. / Zhang, Xinjun; Abreu, Jose Garcia; Yokota, Chika; MacDonald, Bryan T.; Singh, Sasha; Coburn, Karla Loureiro Almeida; Cheong, Seong Moon; Zhang, Mingzi M.; Ye, Qizhuang; Hang, Howard C.; Steen, Hanno; He, Xi.

In: Cell, Vol. 149, No. 7, 22.06.2012, p. 1565-1577.

Research output: Contribution to journalArticle

Zhang, X, Abreu, JG, Yokota, C, MacDonald, BT, Singh, S, Coburn, KLA, Cheong, SM, Zhang, MM, Ye, Q, Hang, HC, Steen, H & He, X 2012, 'Tiki1 is required for head formation via wnt cleavage-oxidation and inactivation', Cell, vol. 149, no. 7, pp. 1565-1577. https://doi.org/10.1016/j.cell.2012.04.039
Zhang X, Abreu JG, Yokota C, MacDonald BT, Singh S, Coburn KLA et al. Tiki1 is required for head formation via wnt cleavage-oxidation and inactivation. Cell. 2012 Jun 22;149(7):1565-1577. https://doi.org/10.1016/j.cell.2012.04.039
Zhang, Xinjun ; Abreu, Jose Garcia ; Yokota, Chika ; MacDonald, Bryan T. ; Singh, Sasha ; Coburn, Karla Loureiro Almeida ; Cheong, Seong Moon ; Zhang, Mingzi M. ; Ye, Qizhuang ; Hang, Howard C. ; Steen, Hanno ; He, Xi. / Tiki1 is required for head formation via wnt cleavage-oxidation and inactivation. In: Cell. 2012 ; Vol. 149, No. 7. pp. 1565-1577.
@article{b46f7ddf308c4377a6faa6ebe7a124ef,
title = "Tiki1 is required for head formation via wnt cleavage-oxidation and inactivation",
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.",
author = "Xinjun Zhang and Abreu, {Jose Garcia} and Chika Yokota and MacDonald, {Bryan T.} and Sasha Singh and Coburn, {Karla Loureiro Almeida} and Cheong, {Seong Moon} and Zhang, {Mingzi M.} and Qizhuang Ye and Hang, {Howard C.} and Hanno Steen and Xi He",
year = "2012",
month = "6",
day = "22",
doi = "10.1016/j.cell.2012.04.039",
language = "English",
volume = "149",
pages = "1565--1577",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "7",

}

TY - JOUR

T1 - Tiki1 is required for head formation via wnt cleavage-oxidation and inactivation

AU - Zhang, Xinjun

AU - Abreu, Jose Garcia

AU - Yokota, Chika

AU - MacDonald, Bryan T.

AU - Singh, Sasha

AU - Coburn, Karla Loureiro Almeida

AU - Cheong, Seong Moon

AU - Zhang, Mingzi M.

AU - Ye, Qizhuang

AU - Hang, Howard C.

AU - Steen, Hanno

AU - He, Xi

PY - 2012/6/22

Y1 - 2012/6/22

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84862684701&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84862684701&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2012.04.039

DO - 10.1016/j.cell.2012.04.039

M3 - Article

C2 - 22726442

AN - SCOPUS:84862684701

VL - 149

SP - 1565

EP - 1577

JO - Cell

JF - Cell

SN - 0092-8674

IS - 7

ER -