TY - JOUR TI - R-spondins can potentiate WNT signaling without LGRs AU - Lebensohn, Andres M AU - Rohatgi, Rajat A2 - Nathans, Jeremy VL - 7 PY - 2018 DA - 2018/02/06 SP - e33126 C1 - eLife 2018;7:e33126 DO - 10.7554/eLife.33126 UR - https://doi.org/10.7554/eLife.33126 AB - The WNT signaling pathway regulates patterning and morphogenesis during development and promotes tissue renewal and regeneration in adults. The R-spondin (RSPO) family of four secreted proteins, RSPO1-4, amplifies target cell sensitivity to WNT ligands by increasing WNT receptor levels. Leucine-rich repeat-containing G-protein coupled receptors (LGRs) 4-6 are considered obligate high-affinity receptors for RSPOs. We discovered that RSPO2 and RSPO3, but not RSPO1 or RSPO4, can potentiate WNT/β-catenin signaling in the absence of all three LGRs. By mapping the domains on RSPO3 that are necessary and sufficient for this activity, we show that the requirement for LGRs is dictated by the interaction between RSPOs and the ZNRF3/RNF43 E3 ubiquitin ligases and that LGR-independent signaling depends on heparan sulfate proteoglycans (HSPGs). We propose that RSPOs can potentiate WNT signals through distinct mechanisms that differ in their use of either LGRs or HSPGs, with implications for understanding their biological functions. KW - R-spondin KW - WNT KW - stem cells KW - heparan sulfate proteoglycans KW - LGR KW - development KW - RSPO KW - ZNRF3 KW - RNF43 KW - HSPG KW - glypican KW - syndecan KW - LGR-independent signaling KW - cancer JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -