Cell
Volume 168, Issue 6, 9 March 2017, Pages 1041-1052.e18
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Article
Decoupling the Functional Pleiotropy of Stem Cell Factor by Tuning c-Kit Signaling

https://doi.org/10.1016/j.cell.2017.02.011Get rights and content
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Highlights

  • An engineered variant of stem cell factor acts as partial agonist of c-Kit

  • SCF partial agonist exhibits biased activation of HSPCs versus mast cells

  • Partial agonist of c-Kit retains therapeutic efficacy but mitigates toxicity in vivo

Summary

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 mechanism-based 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 off-target effects. The approach of biasing cell activation by tuning signaling thresholds and outputs has applications to many dimeric receptor-ligand systems.

Keywords

pleiotropy
stem cell factor
c-Kit
protein engineering
receptor signaling
receptor tyrosine kinase
mast cells
hematopoietic stem cells
anaphylaxis
cytokine

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