title: Discovery of a cytokine and its receptor by functional screening of the extracellular proteome.
abstract: To understand the system of secreted proteins and receptors involved in cell-cell signaling, we produced a comprehensive set of recombinant secreted proteins and the extracellular domains of transmembrane proteins, which constitute most of the protein components of the extracellular space. Each protein was tested in a suite of assays that measured metabolic, growth, or transcriptional responses in diverse cell types. The pattern of responses across assays was analyzed for the degree of functional selectivity of each protein. One of the highly selective proteins was a previously undescribed ligand, designated interleukin-34 (IL-34), which stimulates monocyte viability but does not affect responses in a wide spectrum of other assays. In a separate functional screen, we used a collection of extracellular domains of transmembrane proteins to discover the receptor for IL-34, which was a known cytokine receptor, colony-stimulating factor 1 (also called macrophage colony-stimulating factor) receptor. This systematic approach is thus useful for discovering new ligands and receptors and assessing the functional selectivity of extracellular regulatory proteins.
authors.affiliation: Five Prime Therapeutics, Inc., 1650 Owens Street, Suite 200, San Francisco, CA 94158, USA.
authors.forename: Haishan
authors.initials: H
authors.lastname: Lin
authors.forename: Ernestine
authors.initials: E
authors.lastname: Lee
authors.forename: Kevin
authors.initials: K
authors.lastname: Hestir
authors.forename: Cindy
authors.initials: C
authors.lastname: Leo
authors.forename: Minmei
authors.initials: M
authors.lastname: Huang
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Bosch
authors.forename: Robert
authors.initials: R
authors.lastname: Halenbeck
authors.forename: Ge
authors.initials: G
authors.lastname: Wu
authors.forename: Aileen
authors.initials: A
authors.lastname: Zhou
authors.forename: Dirk
authors.initials: D
authors.lastname: Behrens
authors.forename: Diane
authors.initials: D
authors.lastname: Hollenbaugh
authors.forename: Thomas
authors.initials: T
authors.lastname: Linnemann
authors.forename: Minmin
authors.initials: M
authors.lastname: Qin
authors.forename: Justin
authors.initials: J
authors.lastname: Wong
authors.forename: Keting
authors.initials: K
authors.lastname: Chu
authors.forename: Stephen K
authors.initials: SK
authors.lastname: Doberstein
authors.forename: Lewis T
authors.initials: LT
authors.lastname: Williams
mesh_terms: D000818:Animals; D003001:Cloning, Molecular; D018076:DNA, Complementary; D005110:Extracellular Space / Q000737:chemistry*; D006801:Humans; D007378:Interleukins / Q000302:isolation & purification* / Q000378:metabolism / Q000502:physiology; D008565:Membrane Proteins / Q000302:isolation & purification / Q000502:physiology; D017434:Protein Structure, Tertiary; D020543:Proteome; D018123:Receptors, Interleukin / Q000302:isolation & purification* / Q000502:physiology
chemical_list: D018076:DNA, Complementary; C529076:IL34 protein, human; D007378:Interleukins; D008565:Membrane Proteins; D020543:Proteome; D018123:Receptors, Interleukin; C529075:interleukin-34 receptor, human