RICK Activates a NF-κB-dependent Anti-human Cytomegalovirus Response

Eickhoff, Jan; Hanke, Miriam; Stein-Gerlach, Matthias; Kiang, Tan Poi; Herzberger, Katrin; Habenberger, Peter; Müller, Stefan; Klebl, Bert; Marschall, Manfred; Stamminger, Thomas; Cotten, Matthew

doi:10.1074/jbc.m312893200

Cited by 31 publications

(28 citation statements)

References 56 publications

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“…3A) (24). Expression of the kinase-dead RIP2 form resulted in robust p38 MAPK dual phosphorylation that appears similar to that seen with WT-RIP2, suggesting that kinase activity is not the major contributor.…”

Section: Adenoviral Expression Of Rip2 Increases the Dual Phosphorylamentioning

confidence: 96%

“…Adenoviral Transfection of ARVMs-Adenoviruses encoding HA-tagged forms of wild-type RIP2 (WT-RIP2), kinase-dead RIP2 (DN-RIP2; K47R), CARD-deleted RIP2 (DC-CARD; residues 1-353), and kinase-dead ϩ CARD-deleted RIP2 (DN/DC-RIP2) were as described previously (24) and were added at a multiplicity of infection of 50 when not otherwise specified (providing ϳ95% efficiency of transfection). Cells were exposed to virus for 1 h prior to washing and incubated in virus-free complete M199 medium for 24 h.…”

Section: Products-antibodiesmentioning

confidence: 99%

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The role of RIP2 in p38 MAPK activation in the stressed heart

Jacquet

Nishino

Kumphune

et al. 2008

Journal of Molecular and Cellular Cardiology

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The activation of p38 MAPK by dual phosphorylation aggravates myocardial ischemic injury and depresses cardiac contractile function. SB203580, an ATP-competitive inhibitor of p38 MAPK and other kinases, prevents this dual phosphorylation during ischemia. Studies in non-cardiac tissue have shown receptor-interacting protein 2 (RIP2) lies upstream of p38 MAPK, is SB203580-sensitive and ischemia-responsive, and aggravates ischemic injury. We therefore examined the RIP2-p38 MAPK signaling axis in the heart. Adenovirus-driven expression of wild-type RIP2 in adult rat ventricular myocytes caused robust, SB203580-sensitive dual phosphorylation of p38 MAPK associated with activation of p38 MAPK kinases MKK3, MKK4, and MKK6. The effect of SB203580 was recapitulated by unrelated inhibitors of RIP2 or the downstream MAPK kinase kinase, TAK1. However, overexpression of wild-type, kinasedead, caspase recruitment domain-deleted, or kinase-dead and caspase recruitment domain-deleted forms of RIP2 had no effect on the activating dual phosphorylation of p38 MAPK during simulated ischemia. Similarly, p38 MAPK activation and myocardial infarction size in response to true ischemia did not differ between hearts from wild-type and RIP2 null mice. However, both p38 MAPK activation and the contractile depression caused by the endotoxin component muramyl dipeptide were attenuated by SB203580 and in RIP2 null hearts. Although RIP2 can cause myocardial p38 MAPK dual phosphorylation in the heart under some circumstances, it is not responsible for the SB203580-sensitive pattern of activation during ischemia.There is overwhelming evidence that the activation of p38 MAPK 2 during prolonged myocardial ischemia accelerates injury (see Refs. 1 and 2 for review). Thus, in theory at least, inhibitors of p38 MAPK have therapeutic potential in ischemic heart disease. However, enthusiasm for "blanket" pharmacological inhibition of p38 MAPK is tempered by the facts that it is involved in innumerable biological processes (3), its major isoform is essential for early embryogenesis (4), and hepatic toxicity has curtailed the development of at least three clinical trial programs (5). These drawbacks have increased interest in the mechanisms controlling p38 activation in the hope they will reveal new, less crucial, therapeutic targets (5).The activity of p38 MAPK is controlled by dual phosphorylation of the Thr 180 -Gly 181 -Tyr 182 motif within the activation loop/lip (3). The traditional view is that this dual phosphorylation event is achieved by upstream, dual specificity MAPK kinases or MKKs (3, 5). SB203580 (4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole), a pyridinyl imidazole, is the most widely used pharmacological inhibitor of p38 MAPK. Because it occupies the catalytic site without inhibiting upstream MKKs, it should inhibit the phosphorylation events downstream of p38 MAPK without inhibiting the dual phosphorylation of p38 MAPK itself. Nonetheless, there are numerous examples where SB203580 and other pyridinyl imidazole...

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Section: Adenoviral Expression Of Rip2 Increases the Dual Phosphorylamentioning

confidence: 96%

Section: Products-antibodiesmentioning

confidence: 99%

The role of RIP2 in p38 MAPK activation in the stressed heart

Jacquet

Nishino

Kumphune

et al. 2008

Journal of Molecular and Cellular Cardiology

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“…HeLa, COS-7 and 293, and human foreskin fibroblast (HFF) cells were cultured in DMEM supplemented with 10% fetal bovine serum. Transient transfections of COS-7 and 293 cells were done as previously described (14,15). Plasmids used for transfection experiments were pRK5 constructs expressing human 5-aminoimidazole ribonucleotide carboxylase-4-[(N-succinylamino)carbonyl]-5-aminoimidazole ribonucleotide synthetase (AIRc-SAICARs) or InB kinase-related enzyme TANK-binding kinase 1 (TBK1) fused to a NH 2 -terminal FLAG tag.…”

Section: Methodsmentioning

confidence: 99%

Proteomic Characterization of the Angiogenesis Inhibitor SU6668 Reveals Multiple Impacts on Cellular Kinase Signaling

Godl¹,

Gruß

Eickhoff³

et al. 2005

Cancer Research

Self Cite

102

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Knowledge about molecular drug action is critical for the development of protein kinase inhibitors for cancer therapy. Here, we establish a chemical proteomic approach to profile the anticancer drug SU6668, which was originally designed as a selective inhibitor of receptor tyrosine kinases involved in tumor vascularization. By employing immobilized SU6668 for the affinity capture of cellular drug targets in combination with mass spectrometry, we identified previously unknown targets of SU6668 including Aurora kinases and TANK-binding kinase 1. Importantly, a cell cycle block induced by SU6668 could be attributed to inhibition of Aurora kinase activity. Moreover, SU6668 potently suppressed antiviral and inflammatory responses by interfering with TANK-binding kinase 1-mediated signal transmission. These results show the potential of chemical proteomics to provide rationales for the development of potent kinase inhibitors, which combine rather unexpected biological modes of action by simultaneously targeting defined sets of both serine/threonine and tyrosine kinases involved in cancer progression. (Cancer Res 2005; 65(15): 6919-26)

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“…While the kinase activity of RIP2 was clearly demonstrated, it was unclear whether RIP2 had specific kinase activity toward only serines or threonines. In addition, it was initially thought that the kinase activity of RIP2 was dispensable altogether for NOD2-mediated signal transduction, as kinase-inactive mutants of RIP2 (K47A and D146N) displayed equal or greater capacity to induce NF-kB activation compared with wildtype RIP2 in overexpression systems (Inohara et al 1998;McCarthy et al 1998;Thome et al 1998;Eickhoff et al 2004). However, as the kinase domain makes up ;50%-60% of the RIP2 protein, and as RIP2 is essential for NOD2 signaling, it seems unlikely that the kinase domain is completely inert.…”

mentioning

confidence: 99%

Inhibition of RIP2's tyrosine kinase activity limits NOD2-driven cytokine responses

Tigno-Aranjuez¹,

Asara²,

Abbott³

2010

Genes Dev.

183

197

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Upon intracellular bacterial exposure, the Crohn's disease and sarcoidosis susceptibility protein NOD2 (nucleotide oligomerization domain protein 2) binds to the protein kinase RIP2 (receptor-interacting protein 2) to coordinate NF-kB (nuclear factor k B)-mediated cytokine responses. While RIP2 clearly has kinase activity, the function of its kinase domain has been enigmatic. Although originally classified as a serine-threonine kinase based on homology scans, we find that RIP2 also has tyrosine kinase activity. RIP2 undergoes autophosphorylation on Tyr 474 (Y474). This phosphorylation event is necessary for effective NOD2 signaling and does not occur in the presence of the most common Crohn's disease-associated NOD2 allele. Given this tyrosine kinase activity, a small-molecule inhibitor screen designed to identify pharmacologic agents that inhibit RIP2's tyrosine kinase activity was performed. At nanomolar concentrations, the EGFR (epidermal growth factor receptor) tyrosine kinase inhibitors gefitinib (Iressa) and erlotinib (Tarceva) were found to inhibit both RIP2 tyrosine phosphorylation and MDP (muramyl dipeptide)-induced cytokine release in a variety of NOD2 hyperactivation states. This effect is specific for RIP2 and does not depend on EGFR. The finding that RIP2 has tyrosine kinase activity and the finding that gefitinib and erlotinib, two agents already used clinically for cancer chemotherapy, can inhibit this activity suggest that RIP2's tyrosine kinase activity could be targeted specifically in the treatment of inflammatory diseases.[Keywords: NOD2; RIP2; ITCH; innate immunity; tyrosine kinase] Supplemental material is available at http://www.genesdev.org.

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RICK Activates a NF-κB-dependent Anti-human Cytomegalovirus Response

Abstract: The adapter kinase receptor interacting protein-like interacting caspase-like apoptosis regulatory protein kinase (RICK, also called RIP2 and CARDIAK) was found to be elevated at both the protein and RNA levels during human cytomegalovirus (

Cited by 31 publications

References 56 publications

The role of RIP2 in p38 MAPK activation in the stressed heart

The role of RIP2 in p38 MAPK activation in the stressed heart

Proteomic Characterization of the Angiogenesis Inhibitor SU6668 Reveals Multiple Impacts on Cellular Kinase Signaling

Inhibition of RIP2's tyrosine kinase activity limits NOD2-driven cytokine responses

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