Co-regulation of the transcription controlling ATF2 phosphoswitch by JNK and p38

Kirsch, Klára; Zeke, András; Tőke, Orsolya; Sok, Péter; Sethi, Ashish; Sebő, Anna; Kumar, Ganesan Senthil; Egri, Péter; Póti, Ádám; Gooley, Paul R.; Peti, Wolfgang; Bento, Isabel; Alexa, Anita; Reményi, Attila

doi:10.1038/s41467-020-19582-3

Cited by 40 publications

(29 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, in a recently published double phosphorylated p38α MAPK–Skepinone-L–ATF2 structure (PDB ID: 6zqs), Tyr35 exists in similar configuration as seen in simulations (Supplementary Fig. 5B ) 31 . This provides further rationale for the considerable conformational rearrangement of the G-loop observed in the simulations of 2 .…”

Section: Resultssupporting

confidence: 67%

Decisive role of water and protein dynamics in residence time of p38α MAP kinase inhibitors

et al. 2022

View full text Add to dashboard Cite

Target residence time plays a crucial role in the pharmacological activity of small molecule inhibitors. Little is known, however, about the underlying causes of inhibitor residence time at the molecular level, which complicates drug optimization processes. Here, we employ all-atom molecular dynamics simulations (~400 μs in total) to gain insight into the binding modes of two structurally similar p38α MAPK inhibitors (type I and type I½) with short and long residence times that otherwise show nearly identical inhibitory activities in the low nanomolar IC50 range. Our results highlight the importance of protein conformational stability and solvent exposure, buried surface area of the ligand and binding site resolvation energy for residence time. These findings are further confirmed by simulations with a structurally diverse short residence time inhibitor SB203580. In summary, our data provide guidance in compound design when aiming for inhibitors with improved target residence time.

show abstract

Section: Resultssupporting

confidence: 67%

Decisive role of water and protein dynamics in residence time of p38α MAP kinase inhibitors

et al. 2022

View full text Add to dashboard Cite

show abstract

“…For example, while our approach selected almost all known JNK interactors in our library, it failed to identify the established D-site in the transcription factor ATF2. This is consistent with a recent report that regions of ATF2 outside of its SLiM make an additional contact with MAPKs to increase binding affinity ( 47 ). Likewise, the full p38α-interacting region of the phosphatase PTPN7/HePTP includes additional sequence flanking the canonical D-site ( 48, 49 ), and while enriched in our screen it fell below our hit threshold.…”

Section: Discussionsupporting

confidence: 93%

Proteome-wide screening for mitogen-activated protein kinase docking motifs and interactors

Shi

Robles

Song

et al. 2021

Preprint

View full text Add to dashboard Cite

Essential functions of mitogen-activated protein kinases (MAPKs) depend on their capacity to selectively phosphorylate a limited repertoire of substrates. MAPKs harbor a conserved groove located outside of the catalytic cleft that binds to short linear sequence motifs found in substrates and regulators. However, the weak and transient nature of these “docking” interactions poses a challenge to defining MAPK interactomes and associated sequence motifs. Here, we describe a yeast-based genetic screening pipeline to evaluate large collections of MAPK docking sequences in parallel. Using this platform we analyzed a combinatorial library based on the docking sequences from the MAPK kinases MKK6 and MKK7, defining features critical for binding to the stress-activated MAPKs JNK1 and p38α. We subsequently screened a library consisting of ~12,000 sequences from the human proteome, revealing a large number of MAPK-selective interactors, including many not conforming to previously defined docking motifs. Analysis of p38α/JNK1 exchange mutants identified specific docking groove residues mediating selective binding. Finally, we verified that docking sequences identified in the screen could function in substrate recruitment in vitro and in cultured cells. Collectively, these studies establish an approach for characterization of MAPK docking sequences and provide a resource for future investigation of signaling downstream of p38 and JNK MAP kinases.

show abstract

“…Our study has focused on MK2, one of the bestcharacterized effectors of p38α, but a similar mechanism could operate for other substrates that can associate with p38α in a stable manner, as might be the case for MK3, which contains a similar docking motif to MK2 (50). However, other proteins that interact with p38α seem to be regulated in completely different ways, as shown for MKK6 (18) and ATF2 (51), despite also having a docking motif. It should be noted that the ability of endogenous MK2 to form a stable complex with p38α in nonstimulated cells has not been reported for other substrates.…”

Section: Discussionmentioning

confidence: 87%

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.

View full text Add to dashboard Cite

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.

show abstract

Co-regulation of the transcription controlling ATF2 phosphoswitch by JNK and p38

Cited by 40 publications

References 57 publications

Decisive role of water and protein dynamics in residence time of p38α MAP kinase inhibitors

Decisive role of water and protein dynamics in residence time of p38α MAP kinase inhibitors

Proteome-wide screening for mitogen-activated protein kinase docking motifs and interactors

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

Contact Info

Product

Resources

About