R-spondins can potentiate WNT signaling without LGR receptors

Abstract

6 2 Text 7The WNT signaling pathway regulates patterning and morphogenesis during embryonic 8 development and promotes tissue renewal and regeneration in adults 1,2 . Some WNT responses in 9 vertebrates depend on a second signal provided by the R-spondin family of four secreted proteins 10 (RSPO1-4) that drive the renewal of stem cells in many tissues 3,4 . RSPOs markedly amplify 11 target cell sensitivity to WNT ligands by neutralizing two transmembrane E3 ligases, ZNRF3 12 and RNF43, which reduce cell-surface levels of WNT receptors 5,6 . Chromosomal translocations 13 that increase RSPO expression or that inactivate ZNRF3/RNF43 can drive human cancers 7 . 14 RSPOs contain tandem furin-like repeats (FU1 and FU2), a thrombospondin type I (TSP) 15 domain, and a basic region (BR). RSPOs simultaneously engage ZNRF3/RNF43 through their 16 FU1 domain and one of three leucine-rich repeat-containing G-protein coupled receptors (LGR4-17 6) through their FU2 domain 8-12 , triggering the clearance of ZNRF3/RNF43 and the consequent 18 rise in WNT receptor levels.LGRs are selectively expressed in various tissue stem cells and are 19 considered the primary high-affinity receptors for RSPOs [13][14][15] . Using purified mutant and 20 chimeric RSPOs and cell lines lacking various receptors, we show that RSPO2 and RSPO3, but 21 not RSPO1 and RSPO4, can potentiate WNT/b-catenin signaling in the absence of all three 22

Cancer stem cells, stemness markers and selected drug targeting: metastatic colorectal cancer and cyclooxygenase-2/prostaglandin E2 connection to WNT as a model system

“…LGR5 is a member of the Leucine-rich-repeat-containing G-protein-coupled receptors (also known as GPR49) which belong to the seven transmembraneous G-protein-coupled receptor superfamily. The LGR1-5 family are regulatory receptors involved in WNT signalling [84] and can bind to the furin-like repeat FU2 domains of the R-spondin 1-4 stem cell growth factors to potentiate WNT signalling [85,86] . However, R-spondin 1 (RSPO1)/LGR5 can also directly activate TGFb signalling in a cooperative interaction with the TGFb type II receptor on colon cancer cells to enhance the TGFb-mediated growth inhibition and stress-induced apoptosis [87] .…”

On the implementation and usability of CPO evolution in geodynamic modelling

“…In the polycrystal group there are three classes: full-field models, mean-field homogenization models, and kinematic models. Full field models (e.g., Sarma & Dawson, 1996;Moulinec & Suquet, 1998;A. Lebensohn, 2001) treat both the spatial distribution of continuous grains and the stresses, and allow stress and strain to vary both among and within individual grains in a physically realistic way.…”