Document Detail


PD-1 immunoreceptor inhibits B cell receptor-mediated signaling by recruiting src homology 2-domain-containing tyrosine phosphatase 2 to phosphotyrosine.
MedLine Citation:
PMID:  11698646     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
PD-1 is an immunoreceptor that belongs to the immunoglobulin (Ig) superfamily and contains two tyrosine residues in the cytoplasmic region. Studies on PD-1-deficient mice have shown that PD-1 plays critical roles in establishment and/or maintenance of peripheral tolerance, but the mode of action is totally unknown. To study the molecular mechanism for negative regulation of lymphocytes through the PD-1 receptor, we generated chimeric molecules composed of the IgG Fc receptor type IIB (Fc gamma RIIB) extracellular region and the PD-1 cytoplasmic region and expressed them in a B lymphoma cell line, IIA1.6. Coligation of the cytoplasmic region of PD-1 with the B cell receptor (BCR) in IIA1.6 transformants inhibited BCR-mediated growth retardation, Ca(2+) mobilization, and tyrosine phosphorylation of effector molecules, including Ig beta, Syk, phospholipase C-gamma 2 (PLC gamma 2), and ERK1/2, whereas phosphorylation of Lyn and Dok was not affected. Mutagenesis studies indicated that these inhibitory effects do not require the N-terminal tyrosine in the immunoreceptor tyrosine-based inhibitory motif-like sequence, but do require the other tyrosine residue in the C-terminal tail. This tyrosine was phosphorylated and recruited src homology 2-domain-containing tyrosine phosphatase 2 (SHP-2) on coligation of PD-1 with BCR. These results show that PD-1 can inhibit BCR signaling by recruiting SHP-2 to its phosphotyrosine and dephosphorylating key signal transducers of BCR signaling.
Authors:
T Okazaki; A Maeda; H Nishimura; T Kurosaki; T Honjo
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2001-11-06
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  98     ISSN:  0027-8424     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2001 Nov 
Date Detail:
Created Date:  2001-11-21     Completed Date:  2002-01-08     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  13866-71     Citation Subset:  IM    
Affiliation:
Department of Medical Chemistry, Graduate School of Medicine, Kyoto University, Yoshida-Konoe, Sakyo-ku, Kyoto 606-8501, Japan.
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MeSH Terms
Descriptor/Qualifier:
Animals
Antigens, CD / genetics,  metabolism
Antigens, Surface / genetics,  metabolism*
Apoptosis Regulatory Proteins
Calcium / metabolism
Cell Division
Humans
Intracellular Signaling Peptides and Proteins
Mice
Mitogen-Activated Protein Kinase 1 / metabolism
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinases / metabolism
Phosphorylation
Phosphotyrosine / metabolism*
Protein Phosphatase 2
Protein Tyrosine Phosphatase, Non-Receptor Type 11
Protein Tyrosine Phosphatase, Non-Receptor Type 6
Protein Tyrosine Phosphatases / metabolism*
Receptors, Antigen, B-Cell / metabolism*
Receptors, IgG / genetics,  metabolism
Receptors, Immunologic / genetics,  metabolism*
Receptors, KIR
SH2 Domain-Containing Protein Tyrosine Phosphatases
Signal Transduction*
Tumor Cells, Cultured
Tyrosine / metabolism
src Homology Domains*
Chemical
Reg. No./Substance:
0/Antigens, CD; 0/Antigens, Surface; 0/Apoptosis Regulatory Proteins; 0/Fc gamma receptor IIB; 0/Intracellular Signaling Peptides and Proteins; 0/PD-1 receptor, mouse; 0/Pdcd1 protein, mouse; 0/Receptors, Antigen, B-Cell; 0/Receptors, IgG; 0/Receptors, Immunologic; 0/Receptors, KIR; 146588-21-8/PDCD1 protein, human; 21820-51-9/Phosphotyrosine; 55520-40-6/Tyrosine; 7440-70-2/Calcium; EC 2.7.11.24/Mitogen-Activated Protein Kinase 1; EC 2.7.11.24/Mitogen-Activated Protein Kinase 3; EC 2.7.11.24/Mitogen-Activated Protein Kinases; EC 3.1.3.16/Protein Phosphatase 2; EC 3.1.3.48/PTPN11 protein, human; EC 3.1.3.48/PTPN6 protein, human; EC 3.1.3.48/Protein Tyrosine Phosphatase, Non-Receptor Type 11; EC 3.1.3.48/Protein Tyrosine Phosphatase, Non-Receptor Type 6; EC 3.1.3.48/Protein Tyrosine Phosphatases; EC 3.1.3.48/Ptpn11 protein, mouse; EC 3.1.3.48/Ptpn6 protein, mouse; EC 3.1.3.48/SH2 Domain-Containing Protein Tyrosine Phosphatases
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