ArticleeLife2019
Ancestral reconstruction reveals mechanisms of ERK regulatory evolution.
Article in eLife, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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16 citing papers in PubMed, 31 citations in OpenAlex.
- Critical role of the CMGC insert sequence for tyrosine autophosphorylation in the protein kinase DYRK1B.Scientific reports · 2025Article
- Therapeutic advances of targeting receptor tyrosine kinases in cancer.Signal transduction and targeted therapy · 2024Review
- Ancestral Reconstruction and the Evolution of Protein Energy Landscapes.Annual review of biophysics · 2024Review
- ERK pathway agonism for cancer therapy: evidence, insights, and a target discovery framework.NPJ precision oncology · 2024Review
- Activation Loop Plasticity and Active Site Coupling in the MAP Kinase, ERK2.Journal of molecular biology · 2023Article
- BDNF/TrkB Signaling Inhibition Suppresses Astrogliosis and Alleviates Mechanical Allodynia in a Partial Crush Injury Model.Experimental neurobiology · 2023Article
- Toxoplasma ERK7 protects the apical complex from premature degradation.The Journal of cell biology · 2023Article
- Saturation mutagenesis of a predicted ancestral Syk-family kinase.Protein science : a publication of the Protein Society · 2022Article
- Not your Mother's MAPKs: Apicomplexan MAPK function in daughter cell budding.PLoS pathogens · 2022Review
- Structural analysis of receptor-like kinase SOBIR1 reveals mechanisms that regulate its phosphorylation-dependent activation.Plant communications · 2022Article
- Markov State Models to Study the Functional Dynamics of Proteins in the Wake of Machine Learning.JACS Au · 2021Review
- Deep learning the structural determinants of protein biochemical properties by comparing structural ensembles with DiffNets.Nature communications · 2021Article
- Ancient MAPK ERK7 is regulated by an unusual inhibitory scaffold required forProceedings of the National Academy of Sciences of the United States of America · 2020Article
- Loss of a conserved MAPK causes catastrophic failure in assembly of a specialized cilium-like structure inMolecular biology of the cell · 2020Article
- Review
- Learning from ancestors.eLife · 2019Article
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Authors and funding
9 authors at 4 institutions in 1 country.
Funding
Abstract
Protein kinases are crucial to coordinate cellular decisions and therefore their activities are strictly regulated. Previously we used ancestral reconstruction to determine how CMGC group kinase specificity evolved (Howard et al., 2014). In the present study, we reconstructed ancestral kinases to study the evolution of regulation, from the inferred ancestor of CDKs and MAPKs, to modern ERKs. Kinases switched from high to low autophosphorylation activity at the transition to the inferred ancestor of ERKs 1 and 2. Two synergistic amino acid changes were sufficient to induce this change: shortening of the β3-αC loop and mutation of the gatekeeper residue. Restoring these two mutations to their inferred ancestral state led to a loss of dependence of modern ERKs 1 and 2 on the upstream activating kinase MEK in human cells. Our results shed light on the evolutionary mechanisms that led to the tight regulation of a kinase that is central in development and disease.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.