Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

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


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Protein localization as a principal feature of the etiology and comorbidity of genetic diseases.
S. Park, J.-S. Yang, Y.-E. Shin, J. Park, S. K. Jang, and S. Kim (2014)
Mol Syst Biol 7, 494
   Abstract »    Full Text »    PDF »
Editorial: The emerging specificities of interleukin-34.
E. Solary and N. Droin (2014)
J. Leukoc. Biol. 95, 3-5
   Full Text »    PDF »
CSF-1 receptor-mediated differentiation of a new type of monocytic cell with B cell-stimulating activity: its selective dependence on IL-34.
F. Yamane, Y. Nishikawa, K. Matsui, M. Asakura, E. Iwasaki, K. Watanabe, H. Tanimoto, H. Sano, Y. Fujiwara, E. R. Stanley, et al. (2014)
J. Leukoc. Biol. 95, 19-31
   Abstract »    Full Text »    PDF »
Inhibition of CSF-1 Receptor Improves the Antitumor Efficacy of Adoptive Cell Transfer Immunotherapy.
S. Mok, R. C. Koya, C. Tsui, J. Xu, L. Robert, L. Wu, T. G. Graeber, B. L. West, G. Bollag, and A. Ribas (2014)
Cancer Res. 74, 153-161
   Abstract »    Full Text »    PDF »
Increased Levels of Interleukin 34 in Serum and Synovial Fluid Are Associated with Rheumatoid Factor and Anticyclic Citrullinated Peptide Antibody Titers in Patients with Rheumatoid Arthritis.
S.-J. Moon, Y.-S. Hong, J. H. Ju, S.-K. Kwok, S.-H. Park, and J.-K. Min (2013)
J Rheumatol 40, 1842-1849
   Abstract »    Full Text »    PDF »
Induction of Functional Human Macrophages from Bone Marrow Promonocytes by M-CSF in Humanized Mice.
Y. Li, Q. Chen, D. Zheng, L. Yin, Y. H. Chionh, L. H. Wong, S. Q. Tan, T. C. Tan, J. K. Y. Chan, S. Alonso, et al. (2013)
J. Immunol. 191, 3192-3199
   Abstract »    Full Text »    PDF »
Identification of a Metabolizing Enzyme in Human Kidney by Proteomic Correlation Profiling.
H. Sakurai, K. Kubota, S.-i. Inaba, K. Takanaka, and A. Shinagawa (2013)
Mol. Cell. Proteomics 12, 2313-2323
   Abstract »    Full Text »    PDF »
Receptor-type Protein-tyrosine Phosphatase {zeta} Is a Functional Receptor for Interleukin-34.
S. Nandi, M. Cioce, Y.-G. Yeung, E. Nieves, L. Tesfa, H. Lin, A. W. Hsu, R. Halenbeck, H.-Y. Cheng, S. Gokhan, et al. (2013)
J. Biol. Chem. 288, 21972-21986
   Abstract »    Full Text »    PDF »
IL-34 is overexpressed in the inflamed salivary glands of patients with Sjogren's syndrome and is associated with the local expansion of pro-inflammatory CD14brightCD16+ monocytes.
F. Ciccia, R. Alessandro, V. Rodolico, G. Guggino, S. Raimondo, C. Guarnotta, A. Giardina, G. Sireci, G. Campisi, G. De Leo, et al. (2013)
Rheumatology 52, 1009-1017
   Abstract »    Full Text »    PDF »
CSF1R Signaling Blockade Stanches Tumor-Infiltrating Myeloid Cells and Improves the Efficacy of Radiotherapy in Prostate Cancer.
J. Xu, J. Escamilla, S. Mok, J. David, S. Priceman, B. West, G. Bollag, W. McBride, and L. Wu (2013)
Cancer Res. 73, 2782-2794
   Abstract »    Full Text »    PDF »
Design and pharmacology of a highly specific dual FMS and KIT kinase inhibitor.
C. Zhang, P. N. Ibrahim, J. Zhang, E. A. Burton, G. Habets, Y. Zhang, B. Powell, B. L. West, B. Matusow, G. Tsang, et al. (2013)
PNAS 110, 5689-5694
   Abstract »    Full Text »    PDF »
Colony-stimulating factor 1 receptor (CSF1R) signaling in injured neurons facilitates protection and survival.
J. Luo, F. Elwood, M. Britschgi, S. Villeda, H. Zhang, Z. Ding, L. Zhu, H. Alabsi, R. Getachew, R. Narasimhan, et al. (2013)
J. Exp. Med. 210, 157-172
   Abstract »    Full Text »    PDF »
Increased Serum Interleukin-34 in Patients with Coronary Artery Disease.
Z. Li, D. Jin, Y. Wu, K. Zhang, P. Hu, X. Cao, and Z. Chen (2012)
Journal of International Medical Research 40, 1866-1870
   Abstract »    Full Text »    PDF »
Rescue Screens with Secreted Proteins Reveal Compensatory Potential of Receptor Tyrosine Kinases in Driving Cancer Growth.
F. Harbinski, V. J. Craig, S. Sanghavi, D. Jeffery, L. Liu, K. A. Sheppard, S. Wagner, C. Stamm, A. Buness, C. Chatenay-Rivauday, et al. (2012)
Cancer Discovery 2, 948-959
   Abstract »    Full Text »    PDF »
The molecular profile of microglia under the influence of glioma.
W. Li and M. B. Graeber (2012)
Neuro Oncology 14, 958-978
   Abstract »    Full Text »    PDF »
The management of diffuse-type giant cell tumour (pigmented villonodular synovitis) and giant cell tumour of tendon sheath (nodular tenosynovitis).
L. van der Heijden, C. L. M. H. Gibbons, P. D. S. Dijkstra, J. R. Kroep, C. S. P. van Rijswijk, R. A. Nout, K. M. Bradley, N. A. Athanasou, P. C. W. Hogendoorn, and M. A. J. van de Sande (2012)
Bone Joint J 94-B, 882-888
   Abstract »    Full Text »    PDF »
Spleen serves as a reservoir of osteoclast precursors through vitamin D-induced IL-34 expression in osteopetrotic op/op mice.
Y. Nakamichi, T. Mizoguchi, A. Arai, Y. Kobayashi, M. Sato, J. M. Penninger, H. Yasuda, S. Kato, H. F. DeLuca, T. Suda, et al. (2012)
PNAS 109, 10006-10011
   Abstract »    Full Text »    PDF »
Fos plays an essential role in the upregulation of RANK expression in osteoclast precursors within the bone microenvironment.
A. Arai, T. Mizoguchi, S. Harada, Y. Kobayashi, Y. Nakamichi, H. Yasuda, J. M. Penninger, K. Yamada, N. Udagawa, and N. Takahashi (2012)
J. Cell Sci. 125, 2910-2917
   Abstract »    Full Text »    PDF »
Adult Langerhans cells derive predominantly from embryonic fetal liver monocytes with a minor contribution of yolk sac-derived macrophages.
G. Hoeffel, Y. Wang, M. Greter, P. See, P. Teo, B. Malleret, M. Leboeuf, D. Low, G. Oller, F. Almeida, et al. (2012)
J. Exp. Med. 209, 1167-1181
   Abstract »    Full Text »    PDF »
Macrophage Proliferation Is Regulated through CSF-1 Receptor Tyrosines 544, 559, and 807.
W. Yu, J. Chen, Y. Xiong, F. J. Pixley, Y.-G. Yeung, and E. R. Stanley (2012)
J. Biol. Chem. 287, 13694-13704
   Abstract »    Full Text »    PDF »
HIV-1 Proteins Preferentially Activate Anti-Inflammatory M2-Type Macrophages.
T. Chihara, M. Hashimoto, A. Osman, Y. Hiyoshi-Yoshidomi, I. Suzu, N. Chutiwitoonchai, M. Hiyoshi, S. Okada, and S. Suzu (2012)
J. Immunol. 188, 3620-3627
   Abstract »    Full Text »    PDF »
Aptamers and the RNA World, Past and Present.
L. Gold, N. Janjic, T. Jarvis, D. Schneider, J. J. Walker, S. K. Wilcox, and D. Zichi (2012)
Cold Spring Harb Perspect Biol 4, a003582
   Abstract »    Full Text »    PDF »
Therapeutic applications of macrophage colony-stimulating factor-1 (CSF-1) and antagonists of CSF-1 receptor (CSF-1R) signaling.
D. A. Hume and K. P. A. MacDonald (2012)
Blood 119, 1810-1820
   Abstract »    Full Text »    PDF »
Interleukin 34 expression is associated with synovitis severity in rheumatoid arthritis patients.
M. Chemel, B. Le Goff, R. Brion, C. Cozic, M. Berreur, J. Amiaud, G. Bougras, S. Touchais, F. Blanchard, M. F. Heymann, et al. (2012)
Ann Rheum Dis 71, 150-154
   Abstract »    Full Text »    PDF »
Structural insights into the extracellular assembly of the hematopoietic Flt3 signaling complex.
K. Verstraete, G. Vandriessche, M. Januar, J. Elegheert, A. V. Shkumatov, A. Desfosses, K. Van Craenenbroeck, D. I. Svergun, I. Gutsche, B. Vergauwen, et al. (2011)
Blood 118, 60-68
   Abstract »    Full Text »    PDF »
The mononuclear phagocyte system of the pig as a model for understanding human innate immunity and disease.
L. Fairbairn, R. Kapetanovic, D. P. Sester, and D. A. Hume (2011)
J. Leukoc. Biol. 89, 855-871
   Abstract »    Full Text »    PDF »
Pretransplant CSF-1 therapy expands recipient macrophages and ameliorates GVHD after allogeneic hematopoietic cell transplantation.
D. Hashimoto, A. Chow, M. Greter, Y. Saenger, W.-H. Kwan, M. Leboeuf, F. Ginhoux, J. C. Ochando, Y. Kunisaki, N. van Rooijen, et al. (2011)
J. Exp. Med. 208, 1069-1082
   Abstract »    Full Text »    PDF »
Applications of myeloid-specific promoters in transgenic mice support in vivo imaging and functional genomics but do not support the concept of distinct macrophage and dendritic cell lineages or roles in immunity.
D. A. Hume (2011)
J. Leukoc. Biol. 89, 525-538
   Abstract »    Full Text »    PDF »
BRAF Gene Amplification Can Promote Acquired Resistance to MEK Inhibitors in Cancer Cells Harboring the BRAF V600E Mutation.
R. B. Corcoran, D. Dias-Santagata, K. Bergethon, A. J. Iafrate, J. Settleman, and J. A. Engelman (2010)
Science Signaling 3, ra84
   Abstract »    Full Text »    PDF »
An antibody against the colony-stimulating factor 1 receptor depletes the resident subset of monocytes and tissue- and tumor-associated macrophages but does not inhibit inflammation.
K. P. A. MacDonald, J. S. Palmer, S. Cronau, E. Seppanen, S. Olver, N. C. Raffelt, R. Kuns, A. R. Pettit, A. Clouston, B. Wainwright, et al. (2010)
Blood 116, 3955-3963
   Abstract »    Full Text »    PDF »
Fate Mapping Analysis Reveals That Adult Microglia Derive from Primitive Macrophages.
F. Ginhoux, M. Greter, M. Leboeuf, S. Nandi, P. See, S. Gokhan, M. F. Mehler, S. J. Conway, L. G. Ng, E. R. Stanley, et al. (2010)
Science 330, 841-845
   Abstract »    Full Text »    PDF »
Functional overlap but differential expression of CSF-1 and IL-34 in their CSF-1 receptor-mediated regulation of myeloid cells.
S. Wei, S. Nandi, V. Chitu, Y.-G. Yeung, W. Yu, M. Huang, L. T. Williams, H. Lin, and E. R. Stanley (2010)
J. Leukoc. Biol. 88, 495-505
   Abstract »    Full Text »    PDF »
Editorial: CSF1R, CSF-1, and IL-34, a "menage a trois" conserved across vertebrates.
N. Droin and E. Solary (2010)
J. Leukoc. Biol. 87, 745-747
   Full Text »    PDF »
Pivotal Advance: Avian colony-stimulating factor 1 (CSF-1), interleukin-34 (IL-34), and CSF-1 receptor genes and gene products.
V. Garceau, J. Smith, I. R. Paton, M. Davey, M. A. Fares, D. P. Sester, D. W. Burt, and D. A. Hume (2010)
J. Leukoc. Biol. 87, 753-764
   Abstract »    Full Text »    PDF »
Screening the mammalian extracellular proteome for regulators of embryonic human stem cell pluripotency.
R. Gonzalez, L. L. Jennings, M. Knuth, A. P. Orth, H. E. Klock, W. Ou, J. Feuerhelm, M. V. Hull, E. Koesema, Y. Wang, et al. (2010)
PNAS 107, 3552-3557
   Abstract »    Full Text »    PDF »
Development of Monocytes, Macrophages, and Dendritic Cells.
F. Geissmann, M. G. Manz, S. Jung, M. H. Sieweke, M. Merad, and K. Ley (2010)
Science 327, 656-661
   Abstract »    Full Text »    PDF »
Macrophage differentiation of myeloid progenitor cells in response to M-CSF is regulated by the dual-specificity phosphatase DUSP5.
M.-F. Grasset, S. Gobert-Gosse, G. Mouchiroud, and R. P. Bourette (2010)
J. Leukoc. Biol. 87, 127-135
   Abstract »    Full Text »    PDF »
Automation of the SomaLogic Proteomics Assay: A Platform for Biomarker Discovery.
T. R. Keeney, C. Bock, L. Gold, S. Kraemer, B. Lollo, M. Nikrad, M. Stanton, A. Stewart, J. D. Vaught, and J. J. Walker (2009)
Journal of Laboratory Automation 14, 360-366
   Abstract »    Full Text »    PDF »
CX3CR1+ CD115+ CD135+ common macrophage/DC precursors and the role of CX3CR1 in their response to inflammation.
C. Auffray, D. K. Fogg, E. Narni-Mancinelli, B. Senechal, C. Trouillet, N. Saederup, J. Leemput, K. Bigot, L. Campisi, M. Abitbol, et al. (2009)
J. Exp. Med. 206, 595-606
   Abstract »    Full Text »    PDF »
Colony-stimulating factor-1 (CSF-1) delivers a proatherogenic signal to human macrophages.
K. M. Irvine, M. R. Andrews, M. A. Fernandez-Rojo, K. Schroder, C. J. Burns, S. Su, A. F. Wilks, R. G. Parton, D. A. Hume, and M. J. Sweet (2009)
J. Leukoc. Biol. 85, 278-288
   Abstract »    Full Text »    PDF »
CSF-1 Promoter-Driven IL-34 Expression Can Rescue Phenotypes of CSF-1-Deficient Mice.
S. Wei, H. Lin, and E. R. Stanley (2008)
Blood (ASH Annual Meeting Abstracts) 112, 3867
   Abstract »
IL-34, in Synergy with RANK Ligand, Promotes Osteoclast Development through the CSF-1 Receptor.
M. M. Huang, C. Leo, S. Wei, E. R. Stanley, S. Doberstein, and H. Lin (2008)
Blood (ASH Annual Meeting Abstracts) 112, 5392
   Abstract »
Macrophages as APC and the Dendritic Cell Myth.
D. A. Hume (2008)
J. Immunol. 181, 5829-5835
   Abstract »    Full Text »    PDF »
CSF-1 receptor structure/function in MacCsf1r-/- macrophages: regulation of proliferation, differentiation, and morphology.
W. Yu, J. Chen, Y. Xiong, F. J. Pixley, X.-M. Dai, Y.-G. Yeung, and E. R. Stanley (2008)
J. Leukoc. Biol. 84, 852-863
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882