The Kinase Activity of Rip1 Is Not Required for Tumor Necrosis Factor-α-induced IκB Kinase or p38 MAP Kinase Activation or for the Ubiquitination of Rip1 by Traf2*

By Thomas H. Lee, Jennifer S. Shank, N. Cusson, M. Kelliher. Journal of Biological Chemistry, 2004

156 citations recorded by the source corpus.

The death domain kinase Rip1 is recruited to the tumor necrosis factor receptor type 1 and mediates the IκB kinase and p38 MAP kinase pathways. In response to tumor necrosis factor-α (TNF-α), we find Rip1 phosphorylated and ubiquitinated, suggesting that Rip1 phosphorylation may stimulate its ubiquitination. To address the contribution of the kinase activity of Rip1 to its ubiquitination and to TNF-α signaling, we introduced wild type Rip1 and a kinase-inactive form of Rip1, Rip1D138N, into rip1-/- murine embryonic fibroblast cells by retroviral infection. TNF-α-induced ubiquitination of Rip1 is observed in Rip1D138N cells, supporting the argument that Rip1 autophosphorylation is not required for Rip1 ubiquitination. TNF-α-induced Ikk and p38 MAP kinase activation is normal, and the Rip1D138N cells are resistant to TNF-α-induced cell death, indicating that the kinase activity of Rip1 is not required to mediate its antiapoptotic functions. In the absence of Traf2, TNF-α-induced ubiquitination of Rip1 is impaired, suggesting that Traf2 may be the E3 ubiquitin ligase responsible for the TNF-α-dependent, ubiquitination of Rip1. Finally, recruitment of the ubiquitinated Tak1 complex is dependent on the presence of Rip1, suggesting that Rip1 ubiquitination rather than its phosphorylation is critical in signaling.

Subfields: Cancer Research, Epidemiology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/76c21edb9ef9a94bb4c12a3e2bc4e64acd720a8a

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Citations in the corpus

• Ubiquitylation in innate and adaptive immunity (2009, background): “Genetic studies suggest that TRAF2 is required for RIP1 polyubiquitylation, but there is no direct evidence that TRAF2 or TRAF5 catalyses the ubiquitylation of RIP1 in vitro”
• cIAP1 and cIAP2 facilitate cancer cell survival by functioning as E3 ligases that promote RIP1 ubiquitination. (2008, background): “, 2004) and that TNF-ainduced ubiquitination of RIP1 is impaired in MEFs lacking TRAF2 or in HEK293 cells in which TRAF2 is depleted using siRNA (Lee et al., 2004; Wertz et al., 2004).”