Loss of the tumor suppressor CYLD enhances Wnt/beta-catenin signaling through K63-linked ubiquitination of Dvl.
The mechanism by which Wnt receptors transduce signals to activate downstream beta-catenin-mediated target gene transcription remains incompletely understood but involves Frizzled (Fz) receptor-mediated plasma membrane recruitment and activation of the cytoplasmic effector Dishevelled (Dvl). Here, we identify the deubiquitinating enzyme CYLD, the familial cylindromatosis tumor suppressor gene, as a negative regulator of proximal events in Wnt/beta-catenin signaling. Depletion of CYLD from cultured cells markedly enhances Wnt-induced accumulation of beta-catenin and target gene activation. Moreover, we demonstrate hyperactive Wnt signaling in human cylindroma skin tumors that arise from mutations in CYLD. At the molecular level, CYLD interacts with and regulates K63-linked ubiquitination of Dvl. Enhanced ubiquitination of the polymerization-prone DIX domain in CYLD-deficient cells positively links to the signaling activity of Dvl. Together, our results argue that loss of CYLD instigates tumor growth in human cylindromatosis through a mechanism in which hyperubiquitination of polymerized Dvl drives enhancement of Wnt responses.
Department of Cell Biology, University Medical Center Utrecht, Heidelberglaan 100, 3584CX Utrecht, The Netherlands.
Daniele V F
DV
Tauriello
Andrea
A
Haegebarth
Ineke
I
Kuper
Mariola J
MJ
Edelmann
Marre
M
Henraat
Marijke R
MR
Canninga-van Dijk
Benedikt M
BM
Kessler
Hans
H
Clevers
Madelon M
MM
Maurice
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D003528:Carcinoma, Adenoid Cystic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018280:Carcinoma, Skin Appendage / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D000074749:Deubiquitinating Enzyme CYLD; D000072261:Dishevelled Proteins; D006367:HeLa Cells; D006801:Humans; D008239:Lysine; D051379:Mice; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D055503:Protein Multimerization; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors; D015533:Transcriptional Activation; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D060508:Wnt3 Protein; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; C495270:CTNNB1 protein, human; D000072261:Dishevelled Proteins; D016328:NF-kappa B; D010750:Phosphoproteins; D014409:Tumor Necrosis Factor-alpha; D025521:Tumor Suppressor Proteins; D051153:Wnt Proteins; D060508:Wnt3 Protein; D051176:beta Catenin; C409984:CYLD protein, human; D000074749:Deubiquitinating Enzyme CYLD; D008239:Lysine