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The CD200 receptor (CD200R) acts as a negative regulator of myeloid cells by interacting with its widely expressed ligand CD200. Using mutants expressed in U937 cells, we show that inhibition is mediated by the PTB domain binding motif (NPLY) in the receptor's cytoplasmic region. The adaptor protein downstream of tyrosine kinase 2 (Dok2) bound directly to the phosphorylated NPLY motif with a 10-fold higher affinity (K(D) of approximately 1 microM at 37 degrees C) than the closely related Dok1. Both of these proteins have been suggested to play a role in CD200R signaling in murine cells. Dok2 was phosphorylated in response to CD200R engagement and recruited RAS p21 protein activator 1 (RasGAP). Knockdown of Dok2 and RasGAP by RNA interference revealed that these proteins are required for CD200R signaling, while knockdown of Dok1 and the inositol 5-phosphatase SHIP did not affect CD200R-mediated inhibition. We conclude that CD200R inhibits the activation of human myeloid cells through direct recruitment of Dok2 and subsequent activation of RasGAP, which distinguishes this receptor from the majority of inhibitory receptors that utilize ITIMs and recruit phosphatases.

Original publication

DOI

10.4049/jimmunol.0901531

Type

Journal article

Journal

J Immunol

Publication Date

15/10/2009

Volume

183

Pages

4879 - 4886

Keywords

Adaptor Proteins, Signal Transducing, Animals, Antigens, CD, Antigens, Surface, Cartilage Oligomeric Matrix Protein, Cell Line, Tumor, DNA-Binding Proteins, Extracellular Matrix Proteins, Gene Knockdown Techniques, Glycoproteins, Humans, Interleukin-4, Interleukin-8, Macrophages, Matrilin Proteins, Mice, Myeloid Cells, Phosphoproteins, RNA, Small Interfering, RNA-Binding Proteins, Rats, Receptors, Cell Surface, Signal Transduction, p120 GTPase Activating Protein, ras GTPase-Activating Proteins