Differential activities and mechanisms of the four R-spondins in potentiating Wnt/β-catenin signaling

The Journal of Biological Chemistry
Soohyun ParkQingyun J Liu

Abstract

The four R-spondins (RSPO1-4) strongly potentiate Wnt signaling and play critical roles in normal development, adult stem cell survival, and cancer development and aggressiveness. All four RSPOs have been suggested to potentiate Wnt signaling by binding to three related receptors, i.e. leucine-rich repeat-containing, G protein-coupled receptors 4, 5, and 6 (LGR4/5/6), and then inducing the clearance of two E3 ubiquitin ligases (RNF43 and ZNRF3) that otherwise would ubiquitinate Wnt receptors for degradation. Here, we show that RSPO1-4 have differential dependence on LGRs in potentiating Wnt/β-catenin signaling and that RSPO2 can enhance this pathway without any LGR. LGR4 knockout (LGR4KO) in HEK293 cells completely abrogated the Wnt/β-catenin signaling response to RSPO1 and RSPO4 and strongly impaired the response to RSPO3. RSPO2, however, retained robust activity albeit with decreased potency. Complete rescue of RSPO1-4 activity in LGR4KO cells required the seven-transmembrane domain of LGR4. Furthermore, an RSPO2 mutant with normal binding affinity to ZNRF3 but no or little binding to LGR4 or LGR5 still potentiated Wnt/β-catenin signaling in vitro, supported the growth of intestinal organoids ex vivo, and stimulated intestina...Continue Reading

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Citations

Jan 10, 2020·Journal of Clinical Laboratory Analysis·Tianci ChaiJiangbo Lin
Apr 29, 2019·Cancer Metastasis Reviews·Zhe Wang, Margot Zöller
Apr 25, 2020·Frontiers in Endocrinology·Yentl HuybrechtsWim Van Hul
May 28, 2020·Frontiers in Cell and Developmental Biology·Yong-Ri JinJeong Kyo Yoon
May 30, 2020·EMBO Reports·Valeria Fernandez ValloneMarie-Isabelle Garcia
Aug 23, 2020·International Journal of Molecular Sciences·Chen ShenDavid J Robbins
Oct 22, 2020·International Journal of Molecular Sciences·Malvina KoniMaria Felice Brizzi
Oct 25, 2020·Nature Reviews. Cancer·Jeroen M BugterMadelon M Maurice
Dec 31, 2020·International Journal of Molecular Sciences·Ahmed MalkiAla-Eddin Al Moustafa
Jan 26, 2021·Bioconjugate Chemistry·Songman YuStephen B Howell
Jan 15, 2021·Proceedings of the National Academy of Sciences of the United States of America·Xiaoli LinPeihua Jiang
Sep 23, 2021·American Journal of Physiology. Cell Physiology·Jiajia Pan, Mitchell Ho
Jul 2, 2021·Annual Review of Cell and Developmental Biology·Lauren V AlbrechtEdward M De Robertis

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