Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 288, Issue 30, Pages -Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M112.442731
Keywords
Brain; Cell Surface Receptor; Interleukin; Phosphotyrosine Signaling; Tyrosine Protein Phosphatase (Tyrosine Phosphatase); CSF-1 Receptor; Development; Glioblastoma; Neurobiology; Signal Transduction
Categories
Funding
- National Institutes of Health [CA32551, CA26504, 5P30-CA13330, NS071571, P30HD071593, 1S10RR019352]
- F. M. Kirby Foundation
- Alpern Family Foundation
- Mildred and Bernard H. Kayden Foundation
- Roslyn and Leslie Goldstein Foundation
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Interleukin-34 (IL-34) is highly expressed in brain. IL-34 signaling via its cognate receptor, colony-stimulating factor-1 receptor (CSF-1R), is required for the development of microglia. However, the differential expression of IL-34 and the CSF-1R in brain suggests that IL-34 may signal via an alternate receptor. By IL-34 affinity chromatography of solubilized mouse brain membrane followed by mass spectrometric analysis, we identified receptor-type protein-tyrosine phosphatase (PTP-), a cell surface chondroitin sulfate (CS) proteoglycan, as a novel IL-34 receptor. PTP- is primarily expressed on neural progenitors and glial cells and is highly expressed in human glioblastomas. IL-34 selectively bound PTP- in CSF-1R-deficient U251 human glioblastoma cell lysates and inhibited the proliferation, clonogenicity, and motility of U251 cells in a PTP--dependent manner. These effects were correlated with an increase in tyrosine phosphorylation of the previously identified PTP- downstream effectors focal adhesion kinase and paxillin. IL-34 binding to U251 cells was abrogated by chondroitinase ABC treatment, and CS competed with IL-34 for binding to the extracellular domain of PTP- and to the cells, indicating a dependence of binding on PTP- CS moieties. This study identifies an alternate receptor for IL-34 that may mediate its action on novel cellular targets.
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