Journal
CELL
Volume 168, Issue 6, Pages 1041-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2017.02.011
Keywords
-
Categories
Funding
- Siebel Stem Cell Institute
- Max Kade Fellowship of the Max Kade Foundation
- Austrian Academy of Sciences
- Schroedinger Fellowship of the Austrian Science Fund [FWF: J3399-B21]
- Stanford Molecular and Cellular Immunobiology NIH postdoctoral training grant [5T32 AI072905]
- NIH
- National Cancer Institute
- California Institute for Regenerative Medicine
- Deutsche Forschungsgemeinschaft [SFB 944]
- Ludwig Foundation
- Mathers Foundation
- NIH [RO1-AI51321]
- Howard Hughes Medical Institute
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available