Antigen receptor signal transduction: activating and inhibitory antigen receptors regulate STAT1 serine phosphorylation.
Antigen receptors are crucial regulators of the mammalian immune response. Immediate antigen receptor proximal signal transduction pathways mediated by tyrosine (Tyr) kinases are well defined. In contrast, much less is known about the network of serine (Ser) kinases and Ser kinase substrates that are linked to antigen receptor function. Here we describe a new signaling module for antigen receptors in lymphocytes; a Ser kinase pathway that phosphorylates Ser 727 in STAT1alpha, a member of the signal transducer and activator of transcription gene family. In the present study we have explored the regulation of STAT1 Ser 727 phosphorylation in human T and B lymphocytes and show that it is controlled by both positive and negative antigen receptor signaling cascades. Ligation of antigen receptors in both B and T cells induce a delayed but then sustained phosphorylation of STAT1 on Ser 727. STAT1 Ser phosphorylation is induced by the TCR in the absence of STAT1 Tyr phosphorylation, indicating that in T cells STAT1 Ser and Tyr phosphorylation are independent events. Antigen receptor regulation of STAT Ser phosphorylation is dependent on phosphatidylinositol 3-kinase-mediated signals. Furthermore, the negative regulatory receptor FcgammaRIIb, which mediates vital feedback control of B cell responses, prevents antigen receptor-induced phosphorylation of STAT1 Ser 727. The ability of antigen receptors to both positively and negatively regulate STAT1 Ser 727 phosphorylation reveals a Ser kinase network that operated during sustained responses to antigen receptor engagement.
Vienna Biocenter, Institute of Microbiology and Genetics, Austria.
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Lafont
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Decker
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Cantrell
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000494:pharmacology; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D020935:MAP Kinase Signaling System; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D017452:Receptors, IgG / Q000378:metabolism; D050794:STAT1 Transcription Factor; D012694:Serine / Q000378:metabolism*; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism
D015703:Antigens, CD; D004268:DNA-Binding Proteins; C080571:Fc gamma receptor IIB; D011947:Receptors, Antigen, B-Cell; D011948:Receptors, Antigen, T-Cell; D017452:Receptors, IgG; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C494080:Stat1 protein, mouse; D015534:Trans-Activators; D014443:Tyrosine; D012694:Serine; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D004247:DNA; D019869:Phosphatidylinositol 3-Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases