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.
journal_name
Celljournal_title
Cellauthors
Ho CCM,Chhabra A,Starkl P,Schnorr PJ,Wilmes S,Moraga I,Kwon HS,Gaudenzio N,Sibilano R,Wehrman TS,Gakovic M,Sockolosky JT,Tiffany MR,Ring AM,Piehler J,Weissman IL,Galli SJ,Shizuru JA,Garcia KCdoi
10.1016/j.cell.2017.02.011subject
Has Abstractpub_date
2017-03-09 00:00:00pages
1041-1052.e18issue
6eissn
0092-8674issn
1097-4172pii
S0092-8674(17)30189-7journal_volume
168pub_type
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