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Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors
Koo, Bon-Kyoung,Spit, Maureen,Jordens, Ingrid,Low, Teck Y.,Stange, Daniel E.,van de Wetering, Marc,van Es, Johan H.,Mohammed, Shabaz,Heck, Albert J. R.,Maurice, Madelon M.,Clevers, Hans Nature Publishing Group, a division of Macmillan P 2012 Nature Vol.488 No.7413
LGR5<SUP>+</SUP> stem cells reside at crypt bottoms, intermingled with Paneth cells that provide Wnt, Notch and epidermal growth factor signals. Here we find that the related RNF43 and ZNRF3 transmembrane E3 ubiquitin ligases are uniquely expressed in LGR5<SUP>+</SUP> stem cells. Simultaneous deletion of the two genes encoding these proteins in the intestinal epithelium of mice induces rapidly growing adenomas containing high numbers of Paneth and LGR5<SUP>+</SUP> stem cells. In vitro, growth of organoids derived from these adenomas is arrested when Wnt secretion is inhibited, indicating a dependence of the adenoma stem cells on Wnt produced by adenoma Paneth cells. In the HEK293T human cancer cell line, expression of RNF43 blocks Wnt responses and targets surface-expressed frizzled receptors to lysosomes. In the RNF43-mutant colorectal cancer cell line HCT116, reconstitution of RNF43 expression removes its response to exogenous Wnt. We conclude that RNF43 and ZNRF3 reduce Wnt signals by selectively ubiquitinating frizzled receptors, thereby targeting these Wnt receptors for degradation.
Stange, Daniel E.,Koo, B.K.,Huch, M.,Sibbel, G.,Basak, O.,Lyubimova, A.,Kujala, P.,Bartfeld, S.,Koster, J.,Geahlen, Jessica H.,Peters, Peter J.,van Es, Johan H.,van de Wetering, M.,Mills, Jason C.,Cle Cell Press ; MIT Press 2013 Cell Vol.155 No.2
Proliferation of the self-renewing epithelium of the gastric corpus occurs almost exclusively in the isthmus of the glands, from where cells migrate bidirectionally toward pit and base. The isthmus is therefore generally viewed as the stem cell zone. We find that the stem cell marker Troy is expressed at the gland base by a small subpopulation of fully differentiated chief cells. By lineage tracing with a Troy-eGFP-ires-CreERT2 allele, single marked chief cells are shown to generate entirely labeled gastric units over periods of months. This phenomenon accelerates upon tissue damage. Troy<SUP>+</SUP> chief cells can be cultured to generate long-lived gastric organoids. Troy marks a specific subset of chief cells that display plasticity in that they are capable of replenishing entire gastric units, essentially serving as quiescent ''reserve'' stem cells. These observations challenge the notion that stem cell hierarchies represent a ''one-way street.''