ArticleChemistry & biology2015
Protein kinase d inhibitors uncouple phosphorylation from activity by promoting agonist-dependent activation loop phosphorylation.
Article in Chemistry & biology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 17 citations in OpenAlex.
- ATP-competitive inhibitors of PI3K enzymes demonstrate an isoform selective dual action by controlling membrane binding.The Biochemical journal · 2024Article
- HDAC8 regulates protein kinase D phosphorylation in skeletal myoblasts in response to stress signaling.Biochemical and biophysical research communications · 2023Article
- Statins inhibit protein kinase D (PKD) activation in intestinal cells and prevent PKD1-induced growth of murine enteroids.American journal of physiology. Cell physiology · 2023Article
- Overcoming Paradoxical Kinase Priming by a Novel MNK1 Inhibitor.Journal of medicinal chemistry · 2022Article
- Probing Interdomain Linkers and Protein Supertertiary Structure In Vitro and in Live Cells with Fluorescent Protein Resonance Energy Transfer.Journal of molecular biology · 2021Article
- Small molecule ERK5 kinase inhibitors paradoxically activate ERK5 signalling: be careful what you wish for….Biochemical Society transactions · 2020Review
- Protein kinase D displays intrinsic Tyr autophosphorylation activity: insights into mechanism and regulation.FEBS letters · 2018Article
- The tumor promoter-activated protein kinase Cs are a system for regulating filopodia.Cytoskeleton (Hoboken, N.J.) · 2017Article
- Investigation of the Role of Protein Kinase D in Human Rhinovirus Replication.Journal of virology · 2017Article
- Differential regulation of PKD isoforms in oxidative stress conditions through phosphorylation of a conserved Tyr in the P+1 loop.Scientific reports · 2017Article
- Discovery of a potent protein kinase D inhibitor: insights in the binding mode of pyrazolo[3,4-MedChemComm · 2017Article
- Emergency Spatiotemporal Shift: The Response of Protein Kinase D to Stress Signals in the Cardiovascular System.Frontiers in pharmacology · 2017Review
- An Evolutionarily Conserved PLC-PKD-TFEB Pathway for Host Defense.Cell reports · 2016Article
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
Protein kinase D (PKD) is acutely activated by two tightly coupled events: binding to the second messenger diacylglycerol (DAG) followed by novel protein kinase C (nPKC) phosphorylation at the activation loop and autophosphorylation at the C terminus. Thus, phosphorylation serves as a widely accepted measure of PKD activity. Here we show that treatment of cells with PKD inhibitors paradoxically promotes agonist-dependent activation loop phosphorylation, thus uncoupling phosphorylation from activation. This inhibitor-induced enhancement of phosphorylation differs mechanistically from that previously reported for PKC and Akt, for which active-site inhibitors stabilize a phosphatase-resistant conformation. Rather, a conformational reporter reveals that inhibitor binding induces a conformational change, resulting in relocalization of PKD to basal DAG pools, where it is more readily phosphorylated by nPKCs. These findings illustrate the diverse conformational effects that small molecules exert on their target proteins, underscoring the importance of using caution when interpreting kinase activity from phosphorylation state.
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Registered trials
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.