Molecular mechanisms of CD200 inhibition of mast cell activation.
CD200 and its receptor CD200R are both type I membrane glycoproteins that contain two Ig-like domains. Engagement of CD200R by CD200 inhibits activation of myeloid cells. Unlike the majority of immune inhibitory receptors, CD200R lacks an ITIM in the cytoplasmic domain. The molecular mechanism of CD200R inhibition of myeloid cell activation is unknown. In this study, we examined the CD200R signaling pathways that control degranulation of mouse bone marrow-derived mast cells. We found that upon ligand binding, CD200R is phosphorylated on tyrosine and subsequently binds to adapter proteins Dok1 and Dok2. Upon phosphorylation, Dok1 binds to SHIP and both Dok1 and Dok2 recruit RasGAP, which mediates the inhibition of the Ras/MAPK pathways. Activation of ERK, JNK, and p38 MAPK are all inhibited by CD200R engagement. The reduced activation of these MAPKs is responsible for the observed inhibition of mast cell degranulation and cytokine production. Similar signaling events were also observed upon CD200R engagement in mouse peritoneal cells. These data define a novel inhibitory pathway used by CD200R in modulating mast cell function and help to explain how engagement of this receptor in vivo regulates myeloid cell function.
Zhang
Shuli
S
DNAX Research Institute, Palo Alto, CA 94304, USA.
Cherwinski
Holly
H
Sedgwick
Jonathon D
JD
Phillips
Joseph H
JH
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD; D000954:Antigens, Surface / Q000378:metabolism / Q000502:physiology*; D001854:Bone Marrow Cells / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D015550:Cell Degranulation / Q000276:immunology*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000378:metabolism / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000276:immunology; D008407:Mast Cells / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D010537:Peritoneum / Q000166:cytology / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010750:Phosphoproteins / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding / Q000276:immunology; D016601:RNA-Binding Proteins / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism; D020703:ras GTPase-Activating Proteins / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; D000954:Antigens, Surface; C492346:CD200 receptor, mouse; D004268:DNA-Binding Proteins; C489561:Dok1 protein, mouse; C498444:Dok2 protein, mouse; D007166:Immunosuppressive Agents; D008562:Membrane Glycoproteins; D010750:Phosphoproteins; D016601:RNA-Binding Proteins; D020703:ras GTPase-Activating Proteins; D014443:Tyrosine; D020928:Mitogen-Activated Protein Kinases; D010744:Phosphoric Monoester Hydrolases; C098706:INPPL1 protein, human; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; C042739:antigens, CD200