TY  - JOUR
AU  - Niehrs, Christof
AU  - Seidl, Carina
AU  - Lee, Hyeyoon
TI  - An 'R-spondin code' for multimodal signaling ON-OFF states.
JO  - Bioessays
VL  - 46
IS  - 10
SN  - 0265-9247
CY  - New York, NY
PB  - Wiley-Liss
M1  - DKFZ-2024-01723
SP  - e2400144
PY  - 2024
N1  - #EA:A050#LA:A050# / DKFZ-ZMBH Alliance / 2024 Oct;46(10):e2400144
AB  - 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.
KW  - BMP (Other)
KW  - FGF (Other)
KW  - Hedgehog (Other)
KW  - R‐spondin (Other)
KW  - Wnt (Other)
KW  - axon guidance (Other)
KW  - phosphatases (Other)
KW  - receptor internalization (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:39180250
DO  - DOI:10.1002/bies.202400144
UR  - https://inrepo02.dkfz.de/record/292456
ER  -