Canonical (A) and non-canonical (B) WNT signaling pathways are shown. Both WNT and RSPO ligands synergistically act to generate a maximum activation in canonical WNT signaling. WNT, wingless-type MMTV integration site family; LRP5/6, low density lipoprotein receptor-related protein 5/6; FZD, frizzled; RNF43, ring finger protein 43; ZNRF3, zinc and ring finger 3; LGR, leucine-rich repeat containing G protein-coupled receptor; AXIN, axis inhibition protein; CK1, casein kinase 1; APC, adenomatous polyposis coli; DVL, dishevelled; GSK-3β, glycogen synthase kinase 3 beta; TCF, T-cell factor; RSPO, R-spondin; ROR, retinoic acid-related orphan receptors; RYK, receptor tyrosine kinases; PLC, phospholipase C; PKC, protein kinase C; CDC42, cell division cycle 42; CaN, calcineurin; NFAT, nuclear factor of activated T cells; CaMKII, calcium/calmodulin-dependent protein kinase II; TAK1, TGF-beta-activated kinase 1; NLK, Nemo-like kinase; RAC1, Rac family small GTPase 1; JNK, c-Jun N-terminal kinase; RhoA, ras homolog family member A; ROCK, Rho-associated coiled-coil containing protein kinase.