Decoupling the Functional Pleiotropy of Stem Cell Factor by Tuning c-Kit Signaling
Autor(en): | Ho, Chia Chi M. Chhabra, Akanksha Starkl, Philipp Schnorr, Peter-John Wilmes, Stephan Moraga, Ignacio Kwon, Hye-Sook Gaudenzio, Nicolas Sibilano, Riccardo Wehrman, Tom S. Gakovic, Milica Sockolosky, Jonathan T. Tiffany, Matthew R. Ring, Aaron M. Piehler, Jacob Weissman, Irving L. Galli, Stephen J. Shizuru, Judith A. Garcia, K. Christopher |
Stichwörter: | ACTIVATION; Biochemistry & Molecular Biology; Cell Biology; CYTOKINE PLEIOTROPY; DIMERIZATION; IN-VIVO; LIGAND; MAST-CELL; MICE; PROGENITOR CELLS; RECEPTOR TYROSINE KINASE; STRUCTURAL BASIS | Erscheinungsdatum: | 2017 | Herausgeber: | CELL PRESS | Enthalten in: | CELL | Band: | 168 | Ausgabe: | 6 | Startseite: | 1041+ | Zusammenfassung: | Most secreted growth factors and cytokines are functionally pleiotropic because their receptors are expressed on diverse cell types. While important for normal mammalian physiology, pleiotropy limits the efficacy of cytokines and growth factors as therapeutics. Stem cell factor (SCF) is a growth factor that acts through the c-Kit receptor tyrosine kinase to elicit hematopoietic progenitor expansion but can be toxic when administered in vivo because it concurrently activates mast cells. We engineered a mechanismbased SCF partial agonist that impaired c-Kit dimerization, truncating downstream signaling amplitude. This SCF variant elicited biased activation of hematopoietic progenitors over mast cells in vitro and in vivo. Mouse models of SCF-mediated anaphylaxis, radioprotection, and hematopoietic expansion revealed that this SCF partial agonist retained therapeutic efficacy while exhibiting virtually no anaphylactic offtarget effects. The approach of biasing cell activation by tuning signaling thresholds and outputs has applications to many dimeric receptor-ligand systems. |
ISSN: | 00928674 | DOI: | 10.1016/j.cell.2017.02.011 |
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geprüft am 08.06.2024