MK2 Phosphorylates RIPK1 to Prevent TNF-Induced Cell Death.
Wicky John, S
MetadataShow full item record
TNF is an inflammatory cytokine that upon binding to its receptor, TNFR1, can drive cytokine production, cell survival, or cell death. TNFR1 stimulation causes activation of NF-κB, p38α, and its downstream effector kinase MK2, thereby promoting transcription, mRNA stabilization, and translation of target genes. Here we show that TNF-induced activation of MK2 results in global RIPK1 phosphorylation. MK2 directly phosphorylates RIPK1 at residue S321, which inhibits its ability to bind FADD/caspase-8 and induce RIPK1-kinase-dependent apoptosis and necroptosis. Consistently, a phospho-mimetic S321D RIPK1 mutation limits TNF-induced death. Mechanistically, we find that phosphorylation of S321 inhibits RIPK1 kinase activation. We further show that cytosolic RIPK1 contributes to complex-II-mediated cell death, independent of its recruitment to complex-I, suggesting that complex-II originates from both RIPK1 in complex-I and cytosolic RIPK1. Thus, MK2-mediated phosphorylation of RIPK1 serves as a checkpoint within the TNF signaling pathway that integrates cell survival and cytokine production.
Version of record
Dose-Response Relationship, Drug
Fas-Associated Death Domain Protein
Intracellular Signaling Peptides and Proteins
MAP Kinase Kinase Kinases
Mice, Inbred C57BL
Mitogen-Activated Protein Kinase 14
Receptor-Interacting Protein Serine-Threonine Kinases
Tumor Necrosis Factor-alpha
Cell Death and Inflammation
License start date
Mol Cell, 2017, 66 (5), pp. 698 - 710.e5
Showing items related by title, author, creator and subject.
TGFβ-mediated suppression of CD248 in non-cancer cells via canonical Smad-dependent signaling pathways is uncoupled in cancer cells. Suresh Babu, S; Valdez, Y; Xu, A; O'Byrne, AM; Calvo, F; Lei, V; Conway, EM (2014-01)BACKGROUND: CD248 is a cell surface glycoprotein, highly expressed by stromal cells and fibroblasts of tumors and inflammatory lesions, but virtually undetectable in healthy adult tissues. CD248 promotes tumorigenesis, ...
PARK2 Depletion Connects Energy and Oxidative Stress to PI3K/Akt Activation via PTEN S-Nitrosylation. Gupta, A; Anjomani-Virmouni, S; Koundouros, N; Dimitriadi, M; Choo-Wing, R; Valle, A; Zheng, Y; Chiu, Y-H; Agnihotri, S; Zadeh, G; Asara, JM; Anastasiou, D; Arends, MJ; Cantley, LC; Poulogiannis, G (2017-03-16)PARK2 is a gene implicated in disease states with opposing responses in cell fate determination, yet its contribution in pro-survival signaling is largely unknown. Here we show that PARK2 is altered in over a third of all ...
Stewart, A; Thavasu, P; de Bono, JS; Banerji, U (2015-07)We aimed to understand the relative contributions of inhibiting MEK and AKT on cell growth to guide combinations of these agents.A panel of 20 cell lines was exposed to either the MEK inhibitor, PD0325901, or AKT inhibitor, ...