Expression of a constitutively active p38α mutant in mice causes early death, anemia, and accumulation of immunosuppressive cells

Darlyuk-Saadon, Ilona; Heng, Chew Kiat; Bai, Chen; Gilad, Nechama; Yu, Weiping; Mok, Michelle Meng Huang; Wong, Winnie; Engelberg, David

doi:10.1111/febs.15697

Cited by 4 publications

(2 citation statements)

References 54 publications

(64 reference statements)

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“…However, under conditions of persistent or severe stress (55,56), p38α activation is sustained and MK2 cannot bind to the phosphorylated p38α, leading to irreversible MK2 down-regulation and cell death. Importantly, it has been recently reported that mice expressing a constitutively active p38α mutant show reduced MK2expression levels in several tissues, which correlates with a significant body-weight loss, suggesting that the mechanism of MK2 down-regulation that we propose may also operate in vivo (57). Notably, in response to sustained stress, MDM2 has been reported to show a decreased affinity for phosphorylated p53 (58), suggesting that it could shut down the MK2 pro-survival role without affecting the p53-regulated proapoptotic program.…”

Section: Discussionmentioning

confidence: 58%

MK2 degradation as a sensor of signal intensity that controls stress-induced cell fate

Gutierrez-Prat

Cubillos-Rojas

Cánovas

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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Cell survival in response to stress is determined by the coordination of various signaling pathways. The kinase p38α is activated by many stresses, but the intensity and duration of the signal depends on the stimuli. How different p38α-activation dynamics may impact cell life/death decisions is unclear. Here, we show that the p38α-signaling output in response to stress is modulated by the expression levels of the downstream kinase MK2. We demonstrate that p38α forms a complex with MK2 in nonstimulated mammalian cells. Upon pathway activation, p38α phosphorylates MK2, the complex dissociates, and MK2 is degraded. Interestingly, transient p38α activation allows MK2 reexpression, reassembly of the p38α–MK2 complex, and cell survival. In contrast, sustained p38α activation induced by severe stress interferes with p38α–MK2 interaction, resulting in irreversible MK2 loss and cell death. MK2 degradation is mediated by the E3 ubiquitin ligase MDM2, and we identify four lysine residues in MK2 that are directly ubiquitinated by MDM2. Expression of an MK2 mutant that cannot be ubiquitinated by MDM2 enhances the survival of stressed cells. Our results indicate that MK2 reexpression and binding to p38α is critical for cell viability in response to stress and illustrate how particular p38α-activation patterns induced by different signals shape the stress-induced cell fate.

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Section: Discussionmentioning

confidence: 58%

MK2 degradation as a sensor of signal intensity that controls stress-induced cell fate

Gutierrez-Prat

Cubillos-Rojas

Cánovas

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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“…an ARE-mRNA cis-regulatory binding protein form an intracellular, mutually stabilizing complex and that deletion of p38α or MK2 leads to a reduction of the partner protein due to its destabilization (reviewed in 8). Interestingly, long-term activation of the complex leads to its dissociation and instability of MK2 due to Mdm2-dependent ubiquitination and targeting of MK2 to the proteasome (11); in addition, a transgenic mouse overexpressing constitutively active p38α displays reduced levels of endogenous MK2 (157,158).…”

Section: Kh-type Splicing Regulatory Protein (Ksrp)mentioning

confidence: 99%

MAPK-Activated Protein Kinases: Servant or Partner?

Ronkina

Gaestel

2022

Annu. Rev. Biochem.

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Mitogen-activated protein kinase (MAPK)-activated protein kinases (MAPKAPKs) are defined by their exclusive activation by MAPKs. They can be activated by classical and atypical MAPKs that have been stimulated by mitogens and various stresses. Genetic deletions of MAPKAPKs and availability of highly specific small-molecule inhibitors have continuously increased our functional understanding of these kinases. MAPKAPKs cooperate in the regulation of gene expression at the level of transcription; RNA processing, export, and stability; and protein synthesis. The diversity of stimuli for MAPK activation, the cross talk between the different MAPKs and MAPKAPKs, and the specific substrate pattern of MAPKAPKs orchestrate immediate-early and inflammatory responses in space and time and ensure proper control of cell growth, differentiation, and cell behavior. Hence, MAPKAPKs are promising targets for cancer therapy and treatments for conditions of acute and chronic inflammation, such as cytokine storms and rheumatoid arthritis. Expected final online publication date for the Annual Review of Biochemistry, Volume 91 is June 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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