RNF43 frameshift mutants show enhanced WNT siganling

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R-HSA-5340587
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Reaction [transition]
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Homo sapiens
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Frameshift and missense mutations have been identified in the E3 ubiquitin ligase RNF43 in pancreatic and colorectal cancers, and these trucated, loss of function proteins are believed to be inactive (Ivanov et al, 2007; Koo et al, 2012; Jiang et al, 2013). In wild type cells, RNF43 and the related ZNRF3 protein play a role in down-regulating WNT signaling by ubiquitinating the FZD receptors and promoting their internalization; RNF43 and ZNRF3 are also WNT-target genes, establishing a negative feedback loop (Hao et al, 2012; Mukai et al, 2010; Yagyu et al, 2004; van der Flier et al, 2007). Cells depleted of RNF43 or expressing an oncogenic frameshift mutant are dependent upon stimulation by secreted WNT ligand for their proliferation. Consistent with this, treatment with the Porcupine inhibitor LGK974, which traps WNT in the ER, abrogates the growth of these cells (Koo et al, 2012; Jiang et al, 2013). Depletion of RNF43 results in elevated levels of FZD receptors in the cell membrane and increased expression of WNT reporters and endogenous target genes (Koo et al, 2012; Jiang et al, 2013).

Literature References
PubMed ID Title Journal Year
17320548 The Intestinal Wnt/TCF Signature

Van der Flier, LG, Sabates-Bellver, J, Oving, I, Haegebarth, A, De Palo, M, Anti, M, Van Gijn, ME, Suijkerbuijk, S, van De Wetering, M, Marra, G, Clevers, HC

Gastroenterology 2007
22895187 Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors

Koo, BK, Spit, M, Jordens, I, Low, TY, Stange, DE, van De Wetering, M, van Es, JH, Mohammed, S, Heck, AJ, Maurice, MM, Clevers, HC

Nature 2012
15492824 A novel oncoprotein RNF43 functions in an autocrine manner in colorectal cancer

Yagyu, R, Furukawa, Y, Lin, YM, Shimokawa, T, Yamamura, T, Nakamura, Y

Int. J. Oncol. 2004
22575959 ZNRF3 promotes Wnt receptor turnover in an R-spondin-sensitive manner

Hao, HX, Xie, Y, Zhang, Y, Charlat, O, Oster, E, Avello, M, Lei, H, Mickanin, C, Liu, D, Ruffner, H, Mao, X, Ma, Q, Zamponi, R, Bouwmeester, T, Finan, PM, Kirschner, MW, Porter, JA, Serluca, FC, Cong, F

Nature 2012
20495530 Balanced ubiquitylation and deubiquitylation of Frizzled regulate cellular responsiveness to Wg/Wnt

Mukai, A, Yamamoto-Hino, M, Awano, W, Watanabe, W, Komada, M, Goto, S

EMBO J. 2010
17086209 Identifying candidate colon cancer tumor suppressor genes using inhibition of nonsense-mediated mRNA decay in colon cancer cells

Ivanov, I, Lo, KC, Hawthorn, L, Cowell, JK, Ionov, Y

Oncogene 2007
23847203 Inactivating mutations of RNF43 confer Wnt dependency in pancreatic ductal adenocarcinoma

Jiang, X, Hao, HX, Growney, JD, Woolfenden, S, Bottiglio, C, Ng, N, Lu, B, Hsieh, MH, Bagdasarian, L, Meyer, R, Smith, TR, Avello, M, Charlat, O, Xie, Y, Porter, JA, Pan, S, Liu, J, McLaughlin, ME, Cong, F

Proc. Natl. Acad. Sci. U.S.A. 2013
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Disease
Name Identifier Synonyms
pancreatic cancer 1793 malignant neoplasm of tail of pancreas, pancreatic tumor, Ca body of pancreas, pancreas neoplasm, malignant neoplasm of body of pancreas, pancreatic neoplasm, malignant tumor of body of pancreas (disorder), Ca tail of pancreas (disorder), malignant neoplasm of head of pancreas, Ca tail of pancreas, malignant tumor of tail of pancreas (disorder), neoplasm of pancreas (disorder), Ca head of pancreas, Ca body of pancreas (disorder)
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