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001     292456
005     20250514144601.0
024 7 _ |a 10.1002/bies.202400144
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024 7 _ |a 1521-1878
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037 _ _ |a DKFZ-2024-01723
041 _ _ |a English
082 _ _ |a 540
100 1 _ |a Niehrs, Christof
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245 _ _ |a An 'R-spondin code' for multimodal signaling ON-OFF states.
260 _ _ |a New York, NY
|c 2024
|b Wiley-Liss
336 7 _ |a article
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500 _ _ |a #EA:A050#LA:A050# / DKFZ-ZMBH Alliance / 2024 Oct;46(10):e2400144
520 _ _ |a R-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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650 _ 7 |a BMP
|2 Other
650 _ 7 |a FGF
|2 Other
650 _ 7 |a Hedgehog
|2 Other
650 _ 7 |a R‐spondin
|2 Other
650 _ 7 |a Wnt
|2 Other
650 _ 7 |a axon guidance
|2 Other
650 _ 7 |a phosphatases
|2 Other
650 _ 7 |a receptor internalization
|2 Other
700 1 _ |a Seidl, Carina
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700 1 _ |a Lee, Hyeyoon
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773 _ _ |a 10.1002/bies.202400144
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