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Nature Immunology 9, 186–193 (1 February 2008) | doi:10.1038/ni1548

'Tuning' of type I interferon|[ndash]|induced Jak-STAT1 signaling by calcium-dependent kinases in macrophages

Lu Wang , Ioannis Tassiulas , Kyung-Hyun Park-Min , Alicia C Reid , Hava Gil-Henn , Joseph Schlessinger , Roland Baron , J Jillian Zhang & Lionel B Ivashkiv

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-α-induced Jak activation and STAT1-dependent gene expression. CaMK inhibition suppressed STAT1-mediated interferon-α 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.