R-spondins and LGRs
R-spondin (Rspo) proteins are secreted proteins defined by two N-terminal furin domains and a thrombospondin domain (Kazanskaya et al, 2004; Kim et al, 2005; reviewed in MacDonald and He (2012), Niehrs (2012)). In various contexts, Rspo proteins work synergistically with Wnts to enhance signaling levels but do not activate in the absence of Wnts themselves. Unlike Wnts, which work locally, Rspo proteins have systemic effects. Rspo mutations have been found in several hereditary syndromes in humans (Table below). RSPO1 is disrupted in a recessive syndrome characterized by XX sex reversal, a skin abnormality called palmoplantar hyperkeratosis, and predisposition to squamous cell carcinomas. Mutations in the RSPO4 gene are linked to congenital anonychia, severe hypo- plasia of finger- and toenails.
Rspo proteins use members of the Lgr family as receptors (Glinka et al, 2011, Carmon et al, 2011, De Lau et al, 2011). (see Figure), in particular in stem cells and thereby have input into the canonical Wnt pathway. The receptors are related to G-protein-coupled receptors for thyroid-stimulating hormone, follicle-stimulating hormone and luteinizing hormone. These receptors contain a large N-terminal extracellular leucine-rich repeat domain that binds the glycoprotein hormones. Similarly, the Lgr proteins bind R-spondins through their N-terminal ectodomain, but current evidence indicates that they do not utilize G proteins (Carmon et al, 2011, De Lau et al, 2011).
Lgr4 as well as Lgr5 mutant mice are neonatal lethal. Lgr5 is a Wnt target gene in colon cancer and that it marks adult stem cells in a number of actively self-renewing organs, including the intestinal tract and the hair follicle (reviewed in Clevers and Nusse, 2012) The finding that the Lgr proteins act as receptors for Rspo molecules reinforces the connections between Wnt signaling and activation of adult stem cells.
|RSPO1||Palmoplantar hyperkeratosis||Rspo1||abnormal ovarian development|
|LGR4||Bone density effects||Lgr4||embryonic and perinatal death|
|LGR6||Lgr6||no apparent phenotype|