Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA234353 | ENA |
REPOSITORIES: ENA
Similar Datasets
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Project description:Cell fates regulated by ERK/MAP kinases respond to different thresholds of signaling strength. In mammalian cells, conditions that activate ERK to submaximal levels are sufficient for proliferation, survival and transformation, while stimuli that activate ERK to very high levels often lead to cell death or cell cycle arrest. But while this “Goldilocks effect” is well known, the mechanisms have never been fully explained. In particular, threshold responses have been shown at the level of transcription and cell state changes, but whether phosphorylation responses upstream of these events also respond to thresholds is unknown. Here I used mass spectrometry-based phosphoproteomics to ask if molecular events in the ERK pathway respond to different thresholds of signaling strength, by quantifying changes in phosphorylation of pathway targets against the occupancy of the two activating phosphosites in ERK (2P-ERK). The results show that most phosphorylation events track ERK activation, responding linearly with increasing 2P-ERK occupancy. However, some sites respond nonlinearly, reaching maximal phosphorylation when 2P-ERK exceeds lower thresholds (10-40%), or increasing substantially after 2P-ERK exceeds higher thresholds (>60%). Low threshold sites are found on transcriptional repressors that facilitate proliferation when inactivated by ERK/RSK phosphorylation. In contrast, high threshold sites are found on proteins that are recruited to dsDNA breaks and mediate DNA repair. Measurement of phosphorylation occupancies also revealed unexpected differences between cell states not apparent from inhibitor fold-changes. Our findings demonstrate that signaling thresholds exist at the level of the phosphoproteome, providing potential mechanisms for regulating cellular responses to pathway strength.
2026-02-25 | PXD070673 | panorama
Project description:Cell fates regulated by ERK/MAP kinases respond to different thresholds of signaling strength. In mammalian cells, conditions that activate ERK to submaximal levels are sufficient to sustain proliferation, survival and transformation, while stimuli that activate ERK to very high levels often lead to cell death or cell cycle arrest. But while this “Goldilocks effect” is well known, the mechanisms have never been fully explained. In particular, threshold responses have been shown at the level of transcription and cell state changes, but whether phosphorylation responses upstream of these events also respond to thresholds is unknown. Here we used mass spectrometry-based phosphoproteomics to ask if molecular events in the ERK pathway respond to different thresholds of signaling strength, by quantifying changes in phosphorylation of pathway targets against the occupancy of the two activating phosphosites in ERK. The results show that most phosphorylation events track ERK activation faithfully, responding linearly with increasing 2P-ERK occupancy. But some sites respond nonlinearly, reaching maximal phosphorylation when 2P-ERK exceeds lower thresholds (10-40%), or increasing substantially after 2P-ERK exceeds higher thresholds (>60%). Low threshold sites are found on transcriptional repressors that facilitate proliferation when inactivated by ERK/RSK phosphorylation. By contrast, high threshold sites are found on proteins that are recruited to dsDNA breaks and mediate DNA repair. Measurement of phosphorylation occupancies also revealed unexpected differences between cell states not apparent from inhibitor fold-changes. Our findings demonstrate that signaling thresholds exist at the level of the phosphoproteome, providing potential mechanisms for regulating cellular responses to pathway strength.
2026-02-25 | PXD071012 | Pride
Project description:Cell fates regulated by ERK/MAP kinases respond to different thresholds of signaling strength. In mammalian cells, conditions that activate ERK to submaximal levels are sufficient to sustain proliferation, survival and transformation, while stimuli that activate ERK to very high levels often lead to cell death or cell cycle arrest. But while this “Goldilocks effect” is well known, the mechanisms have never been fully explained. In particular, threshold responses have been shown at the level of transcription and cell state changes, but whether phosphorylation responses upstream of these events also respond to thresholds is unknown. Here we used mass spectrometry-based phosphoproteomics to ask if molecular events in the ERK pathway respond to different thresholds of signaling strength, by quantifying changes in phosphorylation of pathway targets against the occupancy of the two activating phosphosites in ERK. The results show that most phosphorylation events track ERK activation faithfully, responding linearly with increasing 2P-ERK occupancy. But some sites respond nonlinearly, reaching maximal phosphorylation when 2P-ERK exceeds lower thresholds (10-40%), or increasing substantially after 2P-ERK exceeds higher thresholds (>60%). Low threshold sites are found on transcriptional repressors that facilitate proliferation when inactivated by ERK/RSK phosphorylation. By contrast, high threshold sites are found on proteins that are recruited to dsDNA breaks and mediate DNA repair. Measurement of phosphorylation occupancies also revealed unexpected differences between cell states not apparent from inhibitor fold-changes. Our findings demonstrate that signaling thresholds exist at the level of the phosphoproteome, providing potential mechanisms for regulating cellular responses to pathway strength.
2026-02-25 | PXD071061 | Pride
Project description:Cell fates regulated by ERK/MAP kinases respond to different thresholds of signaling strength. In mammalian cells, conditions that activate ERK to submaximal levels are sufficient to sustain proliferation, survival and transformation, while stimuli that activate ERK to very high levels often lead to cell death or cell cycle arrest. But while this “Goldilocks effect” is well known, the mechanisms have never been fully explained. In particular, threshold responses have been shown at the level of transcription and cell state changes, but whether phosphorylation responses upstream of these events also respond to thresholds is unknown. Here we used mass spectrometry-based phosphoproteomics to ask if molecular events in the ERK pathway respond to different thresholds of signaling strength, by quantifying changes in phosphorylation of pathway targets against the occupancy of the two activating phosphosites in ERK. The results show that most phosphorylation events track ERK activation faithfully, responding linearly with increasing 2P-ERK occupancy. But some sites respond nonlinearly, reaching maximal phosphorylation when 2P-ERK exceeds lower thresholds (10-40%), or increasing substantially after 2P-ERK exceeds higher thresholds (>60%). Low threshold sites are found on transcriptional repressors that facilitate proliferation when inactivated by ERK/RSK phosphorylation. By contrast, high threshold sites are found on proteins that are recruited to dsDNA breaks and mediate DNA repair. Measurement of phosphorylation occupancies also revealed unexpected differences between cell states not apparent from inhibitor fold-changes. Our findings demonstrate that signaling thresholds exist at the level of the phosphoproteome, providing potential mechanisms for regulating cellular responses to pathway strength.
2026-02-25 | PXD071074 | Pride
Project description:Cell fates regulated by ERK/MAP kinases respond to different thresholds of signaling strength. In mammalian cells, conditions that activate ERK to submaximal levels are sufficient to sustain proliferation, survival and transformation, while stimuli that activate ERK to very high levels often lead to cell death or cell cycle arrest. But while this “Goldilocks effect” is well known, the mechanisms have never been fully explained. In particular, threshold responses have been shown at the level of transcription and cell state changes, but whether phosphorylation responses upstream of these events also respond to thresholds is unknown. Here we used mass spectrometry-based phosphoproteomics to ask if molecular events in the ERK pathway respond to different thresholds of signaling strength, by quantifying changes in phosphorylation of pathway targets against the occupancy of the two activating phosphosites in ERK. The results show that most phosphorylation events track ERK activation faithfully, responding linearly with increasing 2P-ERK occupancy. But some sites respond nonlinearly, reaching maximal phosphorylation when 2P-ERK exceeds lower thresholds (10-40%), or increasing substantially after 2P-ERK exceeds higher thresholds (>60%). Low threshold sites are found on transcriptional repressors that facilitate proliferation when inactivated by ERK/RSK phosphorylation. By contrast, high threshold sites are found on proteins that are recruited to dsDNA breaks and mediate DNA repair. Measurement of phosphorylation occupancies also revealed unexpected differences between cell states not apparent from inhibitor fold-changes. Our findings demonstrate that signaling thresholds exist at the level of the phosphoproteome, providing potential mechanisms for regulating cellular responses to pathway strength.
2026-02-25 | PXD071110 | Pride
Project description:Kynureninase is a member of a large family of catalytically diverse but structurally homologous pyridoxal 5'-phosphate (PLP) dependent enzymes known as the aspartate aminotransferase superfamily or alpha-family. The Homo sapiens and other eukaryotic constitutive kynureninases preferentially catalyze the hydrolytic cleavage of 3-hydroxy-l-kynurenine to produce 3-hydroxyanthranilate and l-alanine, while l-kynurenine is the substrate of many prokaryotic inducible kynureninases. The human enzyme was cloned with an N-terminal hexahistidine tag, expressed, and purified from a bacterial expression system using Ni metal ion affinity chromatography. Kinetic characterization of the recombinant enzyme reveals classic Michaelis-Menten behavior, with a Km of 28.3 +/- 1.9 microM and a specific activity of 1.75 micromol min-1 mg-1 for 3-hydroxy-dl-kynurenine. Crystals of recombinant kynureninase that diffracted to 2.0 A were obtained, and the atomic structure of the PLP-bound holoenzyme was determined by molecular replacement using the Pseudomonas fluorescens kynureninase structure (PDB entry 1qz9) as the phasing model. A structural superposition with the P. fluorescens kynureninase revealed that these two structures resemble the "open" and "closed" conformations of aspartate aminotransferase. The comparison illustrates the dynamic nature of these proteins' small domains and reveals a role for Arg-434 similar to its role in other AAT alpha-family members. Docking of 3-hydroxy-l-kynurenine into the human kynureninase active site suggests that Asn-333 and His-102 are involved in substrate binding and molecular discrimination between inducible and constitutive kynureninase substrates.
| S-EPMC2531291 | biostudies-literature
Project description:RNA extracted at 240min. Samples are rRNA depleted. Expression measurement of Homo sapiens genes.
2019-07-31 | GSE114179 | GEO
Project description:As the evolution of miRNA genes has been found to be one of the important factors in formation of the modern type of man, we performed a comparative analysis of the evolution of miRNA genes in two archaic hominines, Homo sapiens neanderthalensis and Homo sapiens denisova, and elucidated the expression of their target mRNAs in bain.A comparative analysis of the genomes of primates, including species in the genus Homo, identified a group of miRNA genes having fixed substitutions with important implications for the evolution of Homo sapiens neanderthalensis and Homo sapiens denisova. The mRNAs targeted by miRNAs with mutations specific for Homo sapiens denisova exhibited enhanced expression during postnatal brain development in modern humans. By contrast, the expression of mRNAs targeted by miRNAs bearing variations specific for Homo sapiens neanderthalensis was shown to be enhanced in prenatal brain development.Our results highlight the importance of changes in miRNA gene sequences in the course of Homo sapiens denisova and Homo sapiens neanderthalensis evolution. The genetic alterations of miRNAs regulating the spatiotemporal expression of multiple genes in the prenatal and postnatal brain may contribute to the progressive evolution of brain function, which is consistent with the observations of fine technical and typological properties of tools and decorative items reported from archaeological Denisovan sites. The data also suggest that differential spatial-temporal regulation of gene products promoted by the subspecies-specific mutations in the miRNA genes might have occurred in the brains of Homo sapiens denisova and Homo sapiens neanderthalensis, potentially contributing to the cultural differences between these two archaic hominines.
| S-EPMC4686780 | biostudies-literature