Wnt Signaling through Inhibition of β-Catenin Degradation in an Intact Axin1 Complex

Vivian S W Li, Ser Sue Ng, Paul J. Boersema, Low Teck Yew, Wouter R. Karthaus, Jan P. Gerlach, Shabaz Mohammed, Albert J R Heck, Madelon M. Maurice, Tokameh Mahmoudi, Hans Clevers

Research output: Contribution to journalArticle

428 Citations (Scopus)

Abstract

Degradation of cytosolic β-catenin by the APC/Axin1 destruction complex represents the key regulated step of the Wnt pathway. It is incompletely understood how the Axin1 complex exerts its Wnt-regulated function. Here, we examine the mechanism of Wnt signaling under endogenous levels of the Axin1 complex. Our results demonstrate that β-catenin is not only phosphorylated inside the Axin1 complex, but also ubiquinated and degraded via the proteasome, all within an intact Axin1 complex. In disagreement with current views, we find neither a disassembly of the complex nor an inhibition of phosphorylation of Axin1-bound β-catenin upon Wnt signaling. Similar observations are made in primary intestinal epithelium and in colorectal cancer cell lines carrying activating Wnt pathway mutations. Wnt signaling suppresses β-catenin ubiquitination normally occurring within the complex, leading to complex saturation by accumulated phospho-β-catenin. Subsequently, newly synthesized β-catenin can accumulate in a free cytosolic form and engage nuclear TCF transcription factors.

Original languageEnglish
Pages (from-to)1245-1256
Number of pages12
JournalCell
Volume149
Issue number6
DOIs
Publication statusPublished - 8 Jun 2012
Externally publishedYes

Fingerprint

Catenins
Degradation
Wnt Signaling Pathway
TCF Transcription Factors
Phosphorylation
Ubiquitination
Proteasome Endopeptidase Complex
Intestinal Mucosa
Colorectal Neoplasms
Cells
Cell Line
Mutation

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Li, V. S. W., Ng, S. S., Boersema, P. J., Teck Yew, L., Karthaus, W. R., Gerlach, J. P., ... Clevers, H. (2012). Wnt Signaling through Inhibition of β-Catenin Degradation in an Intact Axin1 Complex. Cell, 149(6), 1245-1256. https://doi.org/10.1016/j.cell.2012.05.002

Wnt Signaling through Inhibition of β-Catenin Degradation in an Intact Axin1 Complex. / Li, Vivian S W; Ng, Ser Sue; Boersema, Paul J.; Teck Yew, Low; Karthaus, Wouter R.; Gerlach, Jan P.; Mohammed, Shabaz; Heck, Albert J R; Maurice, Madelon M.; Mahmoudi, Tokameh; Clevers, Hans.

In: Cell, Vol. 149, No. 6, 08.06.2012, p. 1245-1256.

Research output: Contribution to journalArticle

Li, VSW, Ng, SS, Boersema, PJ, Teck Yew, L, Karthaus, WR, Gerlach, JP, Mohammed, S, Heck, AJR, Maurice, MM, Mahmoudi, T & Clevers, H 2012, 'Wnt Signaling through Inhibition of β-Catenin Degradation in an Intact Axin1 Complex', Cell, vol. 149, no. 6, pp. 1245-1256. https://doi.org/10.1016/j.cell.2012.05.002
Li, Vivian S W ; Ng, Ser Sue ; Boersema, Paul J. ; Teck Yew, Low ; Karthaus, Wouter R. ; Gerlach, Jan P. ; Mohammed, Shabaz ; Heck, Albert J R ; Maurice, Madelon M. ; Mahmoudi, Tokameh ; Clevers, Hans. / Wnt Signaling through Inhibition of β-Catenin Degradation in an Intact Axin1 Complex. In: Cell. 2012 ; Vol. 149, No. 6. pp. 1245-1256.
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