title: Decoupling the Functional Pleiotropy of Stem Cell Factor by Tuning c-Kit Signaling.
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.
authors.affiliation: Department of Bioengineering, Stanford University School of Engineering, 443 Via Ortega, Stanford, CA 94305, USA; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, CA 94305, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, 265 Campus Drive, Stanford, CA 94305, USA.
authors.forename: Chia Chi M
authors.initials: CCM
authors.lastname: Ho
authors.affiliation: Department of Blood and Marrow Transplantation, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, USA; Stanford Cancer Institute, Stanford University School of Medicine, 265 Campus Drive, Stanford, CA 94305, USA.
authors.forename: Akanksha
authors.initials: A
authors.lastname: Chhabra
authors.affiliation: Department of Pathology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, USA; Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria.
authors.forename: Philipp
authors.initials: P
authors.lastname: Starkl
authors.affiliation: Department of Blood and Marrow Transplantation, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, USA; Stanford Cancer Institute, Stanford University School of Medicine, 265 Campus Drive, Stanford, CA 94305, USA.
authors.forename: Peter-John
authors.initials: PJ
authors.lastname: Schnorr
authors.affiliation: Department of Biology, University of Osnabruck, Barbarastr. 11, 49076 Osnabruck, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Wilmes
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University School of Medicine, 279 Campus Drive, Stanford, CA 94305, USA.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Moraga
authors.affiliation: Department of Blood and Marrow Transplantation, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, USA; Stanford Cancer Institute, Stanford University School of Medicine, 265 Campus Drive, Stanford, CA 94305, USA.
authors.forename: Hye-Sook
authors.initials: HS
authors.lastname: Kwon
authors.affiliation: Department of Pathology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, USA.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Gaudenzio
authors.affiliation: Department of Pathology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, USA.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Sibilano
authors.affiliation: Primity Bio, 48383 Fremont Blvd, Suite 118, Fremont, CA 94538, USA.
authors.forename: Tom S
authors.initials: TS
authors.lastname: Wehrman
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, CA 94305, USA.
authors.forename: Milica
authors.initials: M
authors.lastname: Gakovic
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, CA 94305, USA.
authors.forename: Jonathan T
authors.initials: JT
authors.lastname: Sockolosky
authors.affiliation: Department of Pediatrics and Genetics, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, USA.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Tiffany
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, CA 94305, USA; Department of Structural Biology, Stanford University School of Medicine, 299 Campus Drive, Stanford, CA 94305, USA.
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Ring
authors.affiliation: Department of Biology, University of Osnabruck, Barbarastr. 11, 49076 Osnabruck, Germany.
authors.forename: Jacob
authors.initials: J
authors.lastname: Piehler
authors.affiliation: Department of Pathology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, 265 Campus Drive, Stanford, CA 94305, USA; Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine, 265 Campus Drive, Stanford, CA 94305, USA; Stanford Cancer Institute, Stanford University School of Medicine, 265 Campus Drive, Stanford, CA 94305, USA.
authors.forename: Irving L
authors.initials: IL
authors.lastname: Weissman
authors.affiliation: Department of Pathology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, USA; Department of Microbiology and Immunology, Stanford University School of Medicine, 299 Campus Drive, Stanford, CA 94305, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Galli
authors.affiliation: Department of Blood and Marrow Transplantation, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, USA; Stanford Cancer Institute, Stanford University School of Medicine, 265 Campus Drive, Stanford, CA 94305, USA.
authors.forename: Judith A
authors.initials: JA
authors.lastname: Shizuru
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, CA 94305, USA; Department of Structural Biology, Stanford University School of Medicine, 299 Campus Drive, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University School of Medicine, 279 Campus Drive, Stanford, CA 94305, USA. Electronic address: kcgarcia@stanford.edu.
authors.forename: K Christopher
authors.initials: KC
authors.lastname: Garcia
mesh_terms: D000707:Anaphylaxis / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D019281:Dimerization; D006412:Hematopoietic Stem Cells / Q000276:immunology*; D006801:Humans; D008407:Mast Cells / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D015202:Protein Engineering; D019009:Proto-Oncogene Proteins c-kit / Q000819:agonists / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction; D019089:Stem Cell Factor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D019089:Stem Cell Factor; D019009:Proto-Oncogene Proteins c-kit
keywords: anaphylaxis; c-Kit; cytokine; hematopoietic stem cells; mast cells; pleiotropy; protein engineering; receptor signaling; receptor tyrosine kinase; stem cell factor