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Science 320 (5877): 807-811

Copyright © 2008 by the American Association for the Advancement of Science

Discovery of a Cytokine and Its Receptor by Functional Screening of the Extracellular Proteome

Haishan Lin,1 Ernestine Lee,1 Kevin Hestir,1 Cindy Leo,1 Minmei Huang,1 Elizabeth Bosch,1 Robert Halenbeck,1 Ge Wu,1 Aileen Zhou,1 Dirk Behrens,1 Diane Hollenbaugh,1* Thomas Linnemann,1 Minmin Qin,1 Justin Wong,1 Keting Chu,1{dagger} Stephen K. Doberstein,1 Lewis T. Williams1,2{ddagger}

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.

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.

{dagger} Present address: DigitAB, Inc., Burlingame, CA 94010, USA.

{ddagger} To whom correspondence should be addressed. E-mail: rusty.williams{at}fiveprime.com

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