Tighter αC-helix–αL16-helix interactions seem to make p38α less prone to activation by autophosphorylation than Hog1

Tesker, Masha; Selamat, Sadiduddin Edbe; Beenstock, Jonah; Hayouka, Ruchama; Livnah, Oded; Engelberg, David

doi:10.1042/bsr20160020

Cited by 7 publications

(4 citation statements)

References 49 publications

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“…Similar to the assembly mode of this complex, we previously reported that residue W187 of the LeishIF4E-3 core is required for the interaction with LeishIF4G-4 [ 34 ].It now appears that in addition to the core region of LeishIF4E-3, its phosphorylated N-terminus also influences this interaction. It is conceivable that substitution of the S75 phosphorylation site at the N-terminal region could have an allosteric effect on binding to LeishIF4G-4, possibly through alteration in the net charge of LeishIF4E-3 [ 65 , 66 ]. Additionally, the interaction between the mutated LeishIF4E-3 and LeishIF4G-4 was reduced, but not completely diminished.…”

Section: Discussionmentioning

confidence: 99%

Nutritional stress targets LeishIF4E-3 to storage granules that contain RNA and ribosome components in Leishmania

2019

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Leishmania parasites lack pathways for de novo purine biosynthesis. The depletion of purines induces differentiation into virulent metacyclic forms. In vitro, the parasites can survive prolonged periods of purine withdrawal changing their morphology to long and slender cells with an extended flagellum, and decreasing their translation rates. Reduced translation leads to the appearance of discrete granules that contain LeishIF4E-3, one of the six eIF4E paralogs encoded by the Leishmania genome. We hypothesize that each is responsible for a different function during the life cycle. LeishIF4E-3 is a weak cap-binding protein paralog, but its involvement in translation under normal conditions cannot be excluded. However, in response to nutritional stress, LeishIF4E-3 concentrates in specific cytoplasmic granules. LeishIF4E-3 granulation can be induced by the independent elimination of purines, amino acids and glucose. As these granules contain mature mRNAs, we propose that these bodies store inactive transcripts until recovery from stress occurs. In attempt to examine the content of the nutritional stress-induced granules, they were concentrated over sucrose gradients and further pulled-down by targeting in vivo tagged LeishIF4E-3. Proteomic analysis highlighted granule enrichment with multiple ribosomal proteins, suggesting that ribosome particles are abundant in these foci, as expected in case of translation inhibition. RNA-binding proteins, RNA helicases and metabolic enzymes were also enriched in the granules, whereas no degradation enzymes or P-body markers were detected. The starvation-induced LeishIF4E-3-containing granules, therefore, appear to store stalled ribosomes and ribosomal subunits, along with their associated mRNAs. Following nutritional stress, LeishIF4E-3 becomes phosphorylated at position S75, located in its less-conserved N-terminal extension. The ability of the S75A mutant to form granules was reduced, indicating that cellular signaling regulates LeishIF4E-3 function.

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Section: Discussionmentioning

confidence: 99%

Nutritional stress targets LeishIF4E-3 to storage granules that contain RNA and ribosome components in Leishmania

2019

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“…Autophosphorylation is one possibility to be explored. Although MAPKs in general do not show spontaneous autophosphorylation, such capability has been reported for p38β and in other MAPKs it could be de-repressed under specific conditions ( Beenstock et al, 2014 ; Tesker et al, 2016 ).…”

Section: Discussionmentioning

confidence: 71%

SakA and MpkC Stress MAPKs Show Opposite and Common Functions During Stress Responses and Development in Aspergillus nidulans

et al. 2018

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Stress activated MAP kinases (SAPKs) of the Hog1/Sty1/p38 family are specialized in transducing stress signals. In contrast to what is seen in animal cells, very few fungal species contain more than one SAPK. Aspergillus nidulans and other Aspergilli contain two SAPKs called SakA/HogA and MpkC. We have shown that SakA is essential for conidia to maintain their viability and to survive high H2O2 concentrations. H2O2 induces SakA nuclear accumulation and its interaction with transcription factor AtfA. Although SakA and MpkC show physical interaction, little is known about MpkC functions. Here we show that ΔmpkC mutants are not sensitive to oxidative stress but in fact MpkC inactivation partially restores the oxidative stress resistance of ΔsakA mutants. ΔmpkC mutants display about twofold increase in the production of fully viable conidia. The inactivation of the SakA upstream MAPKK PbsB or the simultaneous elimination of sakA and mpkC result in virtually identical phenotypes, including decreased radial growth, a drastic reduction of conidiation and a sharp, progressive loss of conidial viability. SakA and to a minor extent MpkC also regulate cell-wall integrity. Given the roles of MpkC in conidiation and oxidative stress sensitivity, we used a functional MpkC::GFP fusion to determine MpkC nuclear localization as an in vivo indicator of MpkC activation during asexual development and stress. MpkC is mostly localized in the cytoplasm of intact conidia, accumulates in nuclei during the first 2 h of germination and then becomes progressively excluded from nuclei in growing hyphae. In the conidiophore, MpkC nuclear accumulation increases in vesicles, metulae and phialides and decreases in older conidia. Oxidative and osmotic stresses induce MpkC nuclear accumulation in both germinating conidia and hyphae. In all these cases, MpkC nuclear accumulation is largely dependent on the MAPKK PbsB. Our results indicate that SakA and MpkC play major, distinct and sometimes opposing roles in conidiation and conidiospore physiology, as well as common roles in response to stress. We propose that two SAPKs are necessary to delay (MpkC) or fully stop (SakA) mitosis during conidiogenesis and the terminal differentiation of conidia, in the highly prolific phialoconidiation process characteristic of the Aspergilli.

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“…As shown here, intrinsically active ERK mutants are oncoproteins that can induce tissue overgrowth in a scrib mutant tissue, in vivo, raising the question why activating mutations in ERK1/2 have not been identified as cancer drivers. From a structural-functional perspective, it is conceivable that ERK1/ 2 are relatively insensitive to single activating mutations due to their distinctive mode of regulation and/or their unique regulatory domains, which might obstruct self-activation (Beenstock et al 2014(Beenstock et al , 2016Tesker et al 2016). The relative activity of intrinsically active ERK1/2 is, indeed, lower in comparison to MEK-activated ERK1/2, both in vitro as well as in cultured cells (Emrick et al 2001(Emrick et al , 2006Levin-Salomon et al 2008;Goshen-Lago et al 2016).…”

Section: Discussionmentioning

confidence: 99%

An Activating Mutation in ERK Causes Hyperplastic Tumors in ascribbleMutant Tissue inDrosophila

et al. 2020

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Receptor tyrosine kinase signaling plays prominent roles in tumorigenesis, and activating oncogenic point mutations in the core pathway components Ras, Raf, or MEK are prevalent in many types of cancer. Intriguingly, however, analogous oncogenic mutations in the downstream effector kinase ERK have not been described or validated in vivo. To determine if a point mutation could render ERK intrinsically active and oncogenic, we have assayed in Drosophila the effects of a mutation that confers constitutive activity upon a yeast ERK ortholog and has also been identified in a few human tumors. Our analyses indicate that a fly ERK ortholog harboring this mutation alone (Rolled R80S), and more so in conjunction with the known sevenmaker mutation (Rolled R80S+D334N), suppresses multiple phenotypes caused by loss of Ras-Raf-MEK pathway activity, consistent with an intrinsic activity that is independent of upstream signaling. Moreover, expression of Rolled R80S and Rolled R80S+D334N induces tissue overgrowth in an established Drosophila cancer model. Our findings thus demonstrate that activating mutations can bestow ERK with pro-proliferative, tumorigenic capabilities and suggest that Drosophila represents an effective experimental system for determining the oncogenicity of ERK mutants and their response to therapy. KEYWORDS Drosophila; ERK; hyperplastic tumors; oncogenic mutations; rolled RTK signaling; sevenmaker D YSREGULATED Receptor tyrosine kinase (RTK)-mediated signaling has been implicated in diverse human diseases, primarily cancer (

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Tighter αC-helix–αL16-helix interactions seem to make p38α less prone to activation by autophosphorylation than Hog1

Cited by 7 publications

References 49 publications

Nutritional stress targets LeishIF4E-3 to storage granules that contain RNA and ribosome components in Leishmania

Nutritional stress targets LeishIF4E-3 to storage granules that contain RNA and ribosome components in Leishmania

SakA and MpkC Stress MAPKs Show Opposite and Common Functions During Stress Responses and Development in Aspergillus nidulans

An Activating Mutation in ERK Causes Hyperplastic Tumors in ascribbleMutant Tissue inDrosophila

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