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Decoupling the Functional Pleiotropy of Stem Cell Factor by Tuning c-Kit Signaling

Decoupling the Functional Pleiotropy of Stem Cell Factor by Tuning c-Kit Signaling

Chia Chi M Ho, Akanksha Chhabra, Philipp Starkl, Peter-John Schnorr, Stephan Wilmes, Ignacio Moraga, Hye-Sook Kwon, Nicolas Gaudenzio, Riccardo Sibilano, Tom S Wehrman, Milica Gakovic, Jonathan T Sockolosky, etc.

Cell. 2017 Mar 9;168(6):1041-1052.e18.

PMID: 28283060

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR4248641	Stem Cell Factor from mouse			Price

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