R-Spondin Proteins: A Novel Link to β-catenin Activation

Abstract

The R-spondin (Rspo) protein family is a recently described group of four distinct human secreted proteins. Reported activities for Rspo proteins include essential roles in vertebrate development and their ligand-type activities overlap substantially with those of the canonical Wnt ligands in that both Rspo and canonical Wnt signaling result in the activation of beta-catenin. In a general functional screen for human secreted proteins using transgenic mouse models, we identified human R-spondin1 (hRspo1) protein as a potent and specific mitogen for the gastrointestinal epithelium and demonstrated a potential therapeutic application for the protein in mouse models of cancer therapy-induced mucositis. In contrast to previous studies, our data indicated only partial overlap between Wnt and Rspo ligand activities, suggesting that there may be independent receptor/signaling pathways for Rspo proteins that intersect those of Wnt at the level of beta-catenin. Here we summarize the current reported data on the Rspo family and discuss these results in terms of alternate mechanisms of action. We have extended our observations on the potential therapeutic application of Rspo proteins by showing that all four human Rspo family members are capable of inducing epithelial proliferation and report the first non-vertebrate Rspo family member.

R-Spondin1 regulates Wnt signaling by inhibiting internalization of LRP6

“…This prediction is consistent with the expression patterns observed for RSpo family members and Wnt ligands in Xenopus and mouse embryos (15,(19)(20)(21)(22)38). Moreover, we have shown that injection of Rspo proteins into adult mice has a strong mitogenic effect on crypt epithelial cells, whereas no obvious proliferative effects are ob- served in other tissues (16,18). Intestinal crypt proliferation depends on Wnt signaling activity (39)(40)(41)(42)(43), and thus in vivo responses to RSpo proteins appear to be restricted to organs undergoing constitutive Wnt signaling.…”

“…We and others recently described the R-Spondin (RSpo) family of secreted ligands that, similar to canonical Wnt family members, activate ␤-catenin signaling (15)(16)(17)(18). Expression of RSpo proteins overlaps with expression of Wnt ligands during development (15,19), indicating that signaling of RSpo and Wnt proteins may be closely linked.…”

Secreted and Transmembrane Wnt Inhibitors and Activators

“…Subsequently, mouse R-spondin1 (roof plate-specific spondin) was discovered as a gene specifically expressed in the roof plate of the neural tube and the dorsal part of telencephalon (Kamata et al 2004), and Xenopus R-spondin2 was isolated in a functional screen for its property to activate Wnt/b-catenin signaling (Kazanskaya et al 2004). Rspos are evolutionarily conserved and are present also in invertebrates, such as hemichordates, chordates, and echinoderms, but not in Drosophila and C. elegans (Kim et al 2006;Yoon and Lee 2012). In mammals, Rspo1 to -4 show about 60% overall sequence homology and share a signal peptide, two amino-terminal furinlike CRDs, followed by a thrombospondin type-1 domain and a positively charged carboxy-terminal region (Fig.…”

Human SRY inhibits β-catenin-mediated transcription

“…RSPO1 is a small secreted factor that is able to stimulate the canonical Wnt/β-catenin signaling pathway by increasing the levels of a Wnt co-receptor, LRP6 (low density lipoprotein receptorrelated protein 6) at the membrane of the cell (Binnerts et al, 2007, Kazanskaya et al, 2004, Kim et al, 2005, Kim et al, 2006a, Nam et al, 2006. Importantly, the Wnt/β-catenin pathway is active in the early developing ovary and inactive in the early developing testis (Chassot et al, 2008).…”