Cell Biology

Orphan No More?

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Science  15 Jul 2011:
Vol. 333, Issue 6040, pp. 268
DOI: 10.1126/science.333.6040.268-a

The orphan receptors LGR4, LGR5, and LGR6, members of the G protein—coupled receptor family, function in normal development and tumorigenesis. In the intestine and skin, LGR5 and LGR6 represent stem cell markers. Homozygous mouse knockouts of LGR4 exhibit reduced viability and of LGR5 exhibit neonatal lethality. Although much is known about these orphan receptors, the corresponding receptor ligands have eluded detection. Carmon et al. now report that R-spondin, a Wnt antagonist known to stimulate stem cell proliferation, binds LGRs with high affinity and represents the ligand of LGRs 4 to 6. Furthermore, even though LGRs represent members of the G protein–coupled receptors, G proteins are not activated by R-Spondin bound to LGR. Instead it seems that the mechanism for potentiation of Wnt signaling includes rapid internalization of LGRs in a ligand-dependent manner and enhanced β-catenin activity. These findings suggest that stem cell expression of LGR5 and LGR6 and Wnt signaling contribute to stem cell self-renewal and maintenance.

Proc. Natl. Acad. Sci. U.S.A. 10.1073/pnas.1106083108 (2011).

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