Abstract
The kinase RIP1 acts in multiple signaling pathways to regulate inflammatory responses and it can trigger both apoptosis and necroptosis. Its kinase activity has been implicated in a range of inflammatory, neurodegenerative, and oncogenic diseases. Here, we explore the effect of inhibiting RIP1 genetically, using knock-in mice that express catalytically inactive RIP1 D138N, or pharmacologically, using the murine-potent inhibitor GNE684. Inhibition of RIP1 reduced collagen antibody-induced arthritis, and prevented skin inflammation caused by mutation of Sharpin, or colitis caused by deletion of Nemo from intestinal epithelial cells. Conversely, inhibition of RIP1 had no effect on tumor growth or survival in pancreatic tumor models driven by mutant Kras, nor did it reduce lung metastases in a B16 melanoma model. Collectively, our data emphasize a role for the kinase activity of RIP1 in certain inflammatory disease models, but question its relevance to tumor progression and metastases.
Highlights
A cocrystal structure showed that GNE684 binds to the same hydrophobic pocket within the kinase domain of RIP1 that is bound by necrostatins [32] (Fig. 1b, S1, and Table S1)
We evaluated the role of the kinase activity of RIP1 in a mouse model of arthritis that is induced by anticollagen antibodies [40]
Coupled with its favorable pharmacological profile in vivo, GNE684 represents an ideal compound for investigating the physiological role of the kinase activity of RIP1 in disease settings [48,49,50,51,52]
Summary
Oligomerization and translocation of MLKL to cell membranes results in cell lysis [5, 12, 13] In some situations, such as genetic ablation of NEMO (NF-κB essential modulator) [14,15,16], activation of RIP1 instead triggers apoptosis [17, 18]. The kinase activity of RIP1 was shown to limit anti-tumor immunity in pancreatic cancer models [25, 26]. Independent studies have claimed that inhibition of RIP1 prevents tumor cell metastasis [27, 28]. Inhibition of RIP1, either genetically or chemically, had no effect on the growth of pancreatic tumors or on melanoma metastasis. Targeting the kinase activity of RIP1 appears to have more potential as an intervention strategy in inflammatory diseases than in cancer
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