Evidence map›Paper›PMID 30401787›Full record

ArticleScience signaling2018

Engineering allosteric regulation in protein kinases.

David Pincus, Jai P Pandey, Zoë A Feder, Pau Creixell, Orna Resnekov, Kimberly A Reynolds

Abstract read
In one paragraph

Article in Science signaling, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.

0numbers the graph read from it
0cells of the map it votes in
21citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

21 citing papers in PubMed.

  1. Review
  2. Article
  3. Article
  4. Origins of allostery in vertebrate hemoglobin evolution.bioRxiv : the preprint server for biology · 2026
    Article
  5. Article
  6. Article
  7. Article
  8. Perspectives on Synthetic Protein Circuits in Mammalian Cells.Current opinion in biomedical engineering · 2024
    Article
  9. Article
  10. Article
  11. Article
  12. Review
  13. Review
  14. Engineering synthetic phosphorylation signaling networks in human cells.bioRxiv : the preprint server for biology · 2023
    Article
  15. Simple mechanisms for the evolution of protein complexity.Protein science : a publication of the Protein Society · 2022
    Review
  16. Article
  17. Article
  18. Review
  19. A structurally conserved human andProceedings of the National Academy of Sciences of the United States of America · 2020
    Article
  20. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

6 authors.

David PincusWhitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA. pincus@wi.mit.edu kimberly.reynolds@utsouthwestern.edu.
Jai P PandeyWhitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.ORCID 0000-0001-5946-5652
Zoë A FederWhitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
Pau CreixellDavid H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Orna ResnekovCurrently unaffiliated independent scientist.
Kimberly A ReynoldsGreen Center for Systems Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. pincus@wi.mit.edu kimberly.reynolds@utsouthwestern.edu.ORCID 0000-0003-4805-0317

Funding

Quantitative approaches to reveal the homeostatic control mechanisms of stress reDP5OD017941 · OD · WHITEHEAD INSTITUTE FOR BIOMEDICAL RES · PI PINCUS, DAVID · 2013 to 2017
$2.4M
Investigating functional sites in protein kinases as targets for cancer mutations and novel drugsK99CA226396 · NCI · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI CREIXELL, PAU · 2018 to 2019
$266k
NCI NIH HHS K99 CA226396NIH HHS DP5 OD017941
6 · The paper itself

Abstract

Phosphoregulation, in which the addition of a negatively charged phosphate group modulates protein activity, enables dynamic cellular responses. To understand how new phosphoregulation might be acquired, we mutationally scanned the surface of a prototypical yeast kinase (Kss1) to identify potential regulatory sites. The data revealed a set of spatially distributed "hotspots" that might have coevolved with the active site and preferentially modulated kinase activity. By engineering simple consensus phosphorylation sites at these hotspots, we rewired cell signaling in yeast. Using the same approach with a homolog yeast mitogen-activated protein kinase, Hog1, we introduced new phosphoregulation that modified its localization and signaling dynamics. Beyond revealing potential use in synthetic biology, our findings suggest that the identified hotspots contribute to the diversity of natural allosteric regulatory mechanisms in the eukaryotic kinome and, given that some are mutated in cancers, understanding these hotspots may have clinical relevance to human disease.

Indexed as

Allosteric SiteGene Expression Regulation, EnzymologicAllosteric RegulationBinding SitesGene Expression Regulation, FungalMitogen-Activated Protein KinasesMutagenesis, Site-DirectedMutationOsmotic PressurePhosphatesPhosphorylationProtein ConformationProtein EngineeringProtein KinasesSaccharomyces cerevisiaeSaccharomyces cerevisiae ProteinsHOG1 protein, S cerevisiaeKSS1 protein, S cerevisiaeMitogen-Activated Protein KinasesPhosphatesProtein KinasesSaccharomyces cerevisiae Proteins

Identifiers

PMID30401787
PMCPMC6662207

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Registered trials

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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.