'Tuning' of type I interferon-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; Jillian J. Zhang; Lionel B. Ivashkiv

doi:10.1038/ni1548

'Tuning' of type I interferon-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, Jillian J. Zhang, Lionel B. Ivashkiv

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Abstract

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.

Original language	English
Pages (from-to)	186-193
Number of pages	8
Journal	Nature Immunology
Volume	9
Issue number	2
DOIs	https://doi.org/10.1038/ni1548
State	Published - Feb 2008
Externally published	Yes

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title = "'Tuning' of type I interferon-induced Jak-STAT1 signaling by calcium-dependent kinases in macrophages",

abstract = "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.",

author = "Lu Wang and Ioannis Tassiulas and Park-Min, {Kyung Hyun} and Reid, {Alicia C.} and Hava Gil-Henn and Joseph Schlessinger and Roland Baron and Zhang, {Jillian J.} and Ivashkiv, {Lionel B.}",

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AU - Wang, Lu

AU - Tassiulas, Ioannis

AU - Park-Min, Kyung Hyun

AU - Reid, Alicia C.

AU - Gil-Henn, Hava

AU - Schlessinger, Joseph

AU - Baron, Roland

AU - Zhang, Jillian J.

AU - Ivashkiv, Lionel B.

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AB - 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.

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

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