ArticleScientific reports2018
Chk1 KA1 domain auto-phosphorylation stimulates biological activity and is linked to rapid proteasomal degradation.
Article in Scientific reports, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed, 14 citations in OpenAlex.
- CHK1 as a Metabolic and Immunological Regulator: Implications for Cancer Therapy.Oncology research · 2026Review
- Mapping cryptic phosphorylation sites in the human proteome.The EMBO journal · 2025Article
- A structural machine learning approach for rapid prediction of thermodynamically destabilizing tyrosine phosphorylations.Cell reports methods · 2025Article
- Spatiotemporal regulation of MELK during mitosis.Frontiers in cell and developmental biology · 2024Article
- Studying the DNA damage response pathway in hematopoietic canine cancer cell lines, a necessary step for finding targets to generate new therapies to treat cancer in dogs.Frontiers in veterinary science · 2023Article
- CHK1 kinase inhibition: identification of allosteric hits using MD simulations, pharmacophore modeling, docking and MM-PBSA calculations.Molecular diversity · 2022Article
- Structural basis for recruitment of the CHK1 DNA damage kinase by the CLASPIN scaffold protein.Structure (London, England : 1993) · 2021Article
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The DNA damage-activated protein kinase Chk1 is known to undergo auto-phosphorylation, however the sites and functional significance of this modification remain poorly understood. We have identified two novel Chk1 auto-phosphorylation sites, threonines 378 and 382 (T378/382), located in a highly conserved motif within the C-terminal Kinase Associated 1 (KA1) domain. T378/382 occur within optimal consensus Chk1 phosphorylation motifs and substitution with phospho-mimetic aspartic acid residues results in a constitutively active mutant Chk1 kinase (Chk1-DD) that arrests cell cycle progression in G2 phase of the cell cycle in the absence of DNA damage. Remarkably, the mutant Chk1-DD protein is also subject to very rapid proteasomal degradation, with a half-life approximately one tenth that of wild-type Chk1. Consistent with this, T378/T382 auto-phosphorylation also accelerates the proteasomal degradation of constitutively active Chk1 KA1 domain structural mutants. T378/382 auto-phosphorylation and accelerated degradation of wild-type Chk1 occurs at low levels during unperturbed growth, but surprisingly, is not augmented in response to genotoxic stress. Taken together, these observations demonstrate that Chk1 T378/T382 auto-phosphorylation within the KA1 domain is linked to kinase activation and rapid proteasomal degradation, and suggest a non-canonical mechanism of regulation.
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