ArticleMolecular pharmacology2015
Engineering high-potency R-spondin adult stem cell growth factors.
Article in Molecular pharmacology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers, 1 of them a synthesis that pooled it.
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Who cites it
14 citing papers in PubMed, 1 synthesis or guideline pooled it, 19 citations in OpenAlex.
- Guiding Principles: Reporting Elements for Gastrointestinal Organoid Research.Cellular and molecular gastroenterology and hepatology · 2026Guideline
- The oncogenic role of LGR6 overexpression induced by aberrant Wnt/β-catenin signaling in lung cancer.Thoracic cancer · 2024Article
- Time- and cost-efficient bacterial expression and purification of potato apyrase.Protein expression and purification · 2023Article
- Drug Conjugates of Antagonistic R-Spondin 4 Mutant for Simultaneous Targeting of Leucine-Rich Repeat-Containing G Protein-Coupled Receptors 4/5/6 for Cancer Treatment.Journal of medicinal chemistry · 2021Article
- Unlike LGR4, LGR5 potentiates Wnt-β-catenin signaling without sequestering E3 ligases.Science signaling · 2020Article
- Cellular and molecular architecture of the intestinal stem cell niche.Nature cell biology · 2020Review
- Structure-guided engineering of TGF-βs for the development of novel inhibitors and probing mechanism.Bioorganic & medicinal chemistry · 2018Review
- Differential activities and mechanisms of the four R-spondins in potentiating Wnt/β-catenin signaling.The Journal of biological chemistry · 2018Article
- Article
- Probing the Mechanism of Receptor Activity-Modifying Protein Modulation of GPCR Ligand Selectivity through Rational Design of Potent Adrenomedullin and Calcitonin Gene-Related Peptide Antagonists.Molecular pharmacology · 2018Article
- Calcitonin and Amylin Receptor Peptide Interaction Mechanisms: INSIGHTS INTO PEPTIDE-BINDING MODES AND ALLOSTERIC MODULATION OF THE CALCITONIN RECEPTOR BY RECEPTOR ACTIVITY-MODIFYING PROTEINS.The Journal of biological chemistry · 2016Article
- The Aryl Hydrocarbon Receptor Relays Metabolic Signals to Promote Cellular Regeneration.Stem cells international · 2016Review
- Crystal structure of R-spondin 2 in complex with the ectodomains of its receptors LGR5 and ZNRF3.Journal of structural biology · 2015Article
- The interplay between intrinsic and extrinsic Wnt signaling in controlling intestinal transformation.Differentiation; research in biological diversityReview
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Secreted R-spondin proteins (RSPOs1-4) function as adult stem cell growth factors by potentiating Wnt signaling. Simultaneous binding of distinct regions of the RSPO Fu1-Fu2 domain module to the extracellular domains (ECDs) of the LGR4 G protein-coupled receptor and the ZNRF3 transmembrane E3 ubiquitin ligase regulates Wnt receptor availability. Here, we examine the molecular basis for the differing signaling strengths of RSPOs1-4 using purified RSPO Fu1-Fu2, LGR4 ECD, and ZNRF3 ECD proteins in Wnt signaling and receptor binding assays, and we engineer novel high-potency RSPOs. RSPO2/3/4 had similar signaling potencies that were stronger than that of RSPO1, whereas RSPO1/2/3 had similar efficacies that were greater than that of RSPO4. The RSPOs bound LGR4 with affinity rank order RSPO4 > RSPO2/3 > RSPO1 and ZNRF3 with affinity rank order RSPO2/3 > > RSPO1 > RSPO4. An RSPO2-4 chimera combining RSPO2 ZNRF3 binding with RSPO4 LGR4 binding was a "Superspondin" that exhibited enhanced ternary complex formation and 10-fold stronger signaling potency than RSPO2 and efficacy equivalent to RSPO2. An RSPO4-1 chimera combining RSPO4 ZNRF3 binding with RSPO1 LGR4 binding was a "Poorspondin" that exhibited signaling potency similar to RSPO1 and efficacy equivalent to RSPO4. Conferring increased ZNRF3 binding upon RSPO4 with amino acid substitutions L56F, I58L, and I63M enhanced its signaling potency and efficacy. Our results reveal the molecular basis for RSPOs1-4 activity differences and suggest that signaling potency is determined by ternary complex formation ability, whereas efficacy depends on ZNRF3 recruitment. High-potency RSPOs may be of value for regenerative medicine and/or therapeutic applications.
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