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000292456 1001_ $$0P:(DE-He78)483ad6be7d7fe19e48db9cce86efd70e$$aNiehrs, Christof$$b0$$eFirst author$$udkfz
000292456 245__ $$aAn 'R-spondin code' for multimodal signaling ON-OFF states.
000292456 260__ $$aNew York, NY$$bWiley-Liss$$c2024
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000292456 500__ $$a#EA:A050#LA:A050# / DKFZ-ZMBH Alliance / 2024 Oct;46(10):e2400144
000292456 520__ $$aR-spondins (RSPOs) are a family of secreted proteins and stem cell growth factors that are potent co-activators of Wnt signaling. Recently, RSPO2 and RSPO3 were shown to be multifunctional, not only amplifying Wnt- but also binding BMP- and FGF receptors to downregulate signaling. The common mechanism underlying these diverse functions is that RSPO2 and RSPO3 act as 'endocytosers' that link transmembrane proteins to ZNRF3/RNF43 E3 ligases and trigger target internalization. Thus, RSPOs are natural protein targeting chimeras for cell surface proteins. Conducting data mining and cell surface binding assays we report additional candidate RSPO targets, including SMO, PTC1,2, LGI1, ROBO4, and PTPR(F/S). We propose that there is an 'R-spondin code' that imparts combinatorial signaling ON-OFF states of multiple growth factors. This code involves the modular RSPO domains, notably distinct motifs in the divergent RSPO-TSP1 domains to mediate target interaction and internalization. The RSPO code offers a novel framework for the understanding how diverse signaling pathways may be coordinately regulated in development and disease.
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000292456 650_7 $$2Other$$aBMP
000292456 650_7 $$2Other$$aFGF
000292456 650_7 $$2Other$$aHedgehog
000292456 650_7 $$2Other$$aR‐spondin
000292456 650_7 $$2Other$$aWnt
000292456 650_7 $$2Other$$aaxon guidance
000292456 650_7 $$2Other$$aphosphatases
000292456 650_7 $$2Other$$areceptor internalization
000292456 7001_ $$0P:(DE-He78)5b895ce811cc43507affc3795b4decab$$aSeidl, Carina$$b1
000292456 7001_ $$0P:(DE-He78)b2253633681399146975628b760ff3e0$$aLee, Hyeyoon$$b2$$eLast author$$udkfz
000292456 773__ $$0PERI:(DE-600)1473795-4$$a10.1002/bies.202400144$$gp. 2400144$$n10$$pe2400144$$tBioessays$$v46$$x0265-9247$$y2024
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