'Tuning' of type I interferon-induced Jak-STAT1 signaling by calcium-dependent kinases in macrophages.
Immunoreceptor tyrosine-based activation motif (ITAM)-coupled receptors modulate the amplitude and nature of macrophage responses to Toll-like receptor and cytokine receptor stimulation. However, the molecular mechanisms enabling this receptor crosstalk are not known. Here we investigated the function of the calcium-dependent kinases CaMK and Pyk2 'downstream' of ITAM-associated receptors in the regulation of cytokine-induced activation of Jak kinases and STAT transcription factors. CaMK and Pyk2 relayed signals from integrins and the ITAM-containing adaptor DAP12 to augment interleukin 10- and interferon-alpha-induced Jak activation and STAT1-dependent gene expression. CaMK inhibition suppressed STAT1-mediated interferon-alpha signaling in a mouse model of systemic lupus erythematosus. Our results associate Pyk2 and Jak kinases with the linkage of signals emanating from cytokine and heterologous ITAM-dependent receptors.
Wang
Lu
L
Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, New York 10021, USA.
Tassiulas
Ioannis
I
Park-Min
Kyung-Hyun
KH
Reid
Alicia C
AC
Gil-Henn
Hava
H
Schlessinger
Joseph
J
Baron
Roland
R
Zhang
J Jillian
JJ
Ivashkiv
Lionel B
LB
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002118:Calcium / Q000378:metabolism; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000378:metabolism*; D002478:Cells, Cultured; D051418:Focal Adhesion Kinase 2 / Q000378:metabolism*; D006801:Humans; D007370:Interferon Type I / Q000494:pharmacology*; D053612:Janus Kinases / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology; D008565:Membrane Proteins; D051379:Mice; D010766:Phosphorylation; D011971:Receptors, Immunologic / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D007370:Interferon Type I; D008565:Membrane Proteins; D011971:Receptors, Immunologic; D050794:STAT1 Transcription Factor; C110546:TYROBP protein, human; D014443:Tyrosine; D051418:Focal Adhesion Kinase 2; D053612:Janus Kinases; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D002118:Calcium