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Discovery of a Cytokine and Its Receptor by Functional Screening of the Extracellular Proteome
Haishan Lin,1Ernestine Lee,1Kevin Hestir,1Cindy Leo,1Minmei Huang,1Elizabeth Bosch,1Robert Halenbeck,1Ge Wu,1Aileen Zhou,1Dirk Behrens,1Diane Hollenbaugh,1*Thomas Linnemann,1Minmin Qin,1Justin Wong,1Keting Chu,1Stephen K. Doberstein,1Lewis T. Williams1,2
To understand the system of secreted proteins and receptorsinvolved in cell-cell signaling, we produced a comprehensiveset of recombinant secreted proteins and the extracellular domainsof transmembrane proteins, which constitute most of the proteincomponents of the extracellular space. Each protein was testedin a suite of assays that measured metabolic, growth, or transcriptionalresponses in diverse cell types. The pattern of responses acrossassays was analyzed for the degree of functional selectivityof each protein. One of the highly selective proteins was apreviously undescribed ligand, designated interleukin-34 (IL-34),which stimulates monocyte viability but does not affect responsesin a wide spectrum of other assays. In a separate functionalscreen, we used a collection of extracellular domains of transmembraneproteins to discover the receptor for IL-34, which was a knowncytokine receptor, colony-stimulating factor 1 (also calledmacrophage colony-stimulating factor) receptor. This systematicapproach is thus useful for discovering new ligands and receptorsand assessing the functional selectivity of extracellular regulatoryproteins.
1 Five Prime Therapeutics, Inc., 1650 Owens Street, Suite 200, San Francisco, CA 94158, USA. 2 School of Medicine, University of California, San Francisco, CA 94143, USA.
* Present address: Schering-Plough Biopharma, Palo Alto, CA 94304,USA.
Present address: DigitAB, Inc., Burlingame, CA 94010, USA.
To whom correspondence should be addressed. E-mail: rusty.williams{at}fiveprime.com
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Present address: DigitAB, Inc., Burlingame, CA 94010, USA. 
To whom correspondence should be addressed. E-mail: 
