ArticleThe Journal of biological chemistry2016
Protein Scaffolds Control Localized Protein Kinase Cζ Activity.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 38 citations in OpenAlex.
- Sensitive fluorescent biosensor reveals differential subcellular regulation of PKC.Nature chemical biology · 2025Article
- A Gallbladder-Specific Hydrophobic Bile Acid-FXR-MUC1 Signaling Axis Mediates Cholesterol Gallstone Formation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Sensitive Fluorescent Biosensor Reveals Differential Subcellular Regulation of PKC.bioRxiv : the preprint server for biology · 2024Article
- The mTORC2 signaling network: targets and cross-talks.The Biochemical journal · 2024Review
- Tethering ATG16L1 or LC3 induces targeted autophagic degradation of protein aggregates and mitochondria.Autophagy · 2023Article
- A Multimodel Study of the Role of Novel PKC Isoforms in the DNA Integrity Checkpoint.International journal of molecular sciences · 2023Article
- Loss of polarity regulators initiates gasdermin-E-mediated pyroptosis in syncytiotrophoblasts.Life science alliance · 2023Article
- Protein kinase C: release from quarantine by mTORC2.Trends in biochemical sciences · 2022Review
- Conventional protein kinase C in the brain: repurposing cancer drugs for neurodegenerative treatment?Neuronal signaling · 2021Review
- Biochemical Activity Architectures Visualized-Using Genetically Encoded Fluorescent Biosensors to Map the Spatial Boundaries of Signaling Compartments.Accounts of chemical research · 2021Review
- Signaling Microdomains in the Spotlight: Visualizing Compartmentalized Signaling Using Genetically Encoded Fluorescent Biosensors.Annual review of pharmacology and toxicology · 2021Review
- Equivocal, explicit and emergent actions of PKC isoforms in cancer.Nature reviews. Cancer · 2021Review
- Role of Protein Kinase C in Immune Cell Activation and Its Implication Chemical-Induced Immunotoxicity.Advances in experimental medicine and biology · 2021Article
- EnteropathogenicInternational journal of molecular sciences · 2020Article
- Bidirectional Regulation of Opioid and Chemokine Function.Frontiers in immunology · 2020Review
- aPKC in neuronal differentiation, maturation and function.Neuronal signaling · 2019Review
- Experiments with Snails Add to Our Knowledge about the Role of aPKC Subfamily Kinases in Learning.International journal of molecular sciences · 2019Article
- Apical-basal polarity inhibits epithelial-mesenchymal transition and tumour metastasis by PAR-complex-mediated SNAI1 degradation.Nature cell biology · 2019Article
- Activation of atypical protein kinase C by sphingosine 1-phosphate revealed by an aPKC-specific activity reporter.Science signaling · 2019Article
- Genetically Encoded Fluorescent Biosensors Illuminate the Spatiotemporal Regulation of Signaling Networks.Chemical reviews · 2018Review
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
Atypical protein kinase C (aPKC) isozymes modulate insulin signaling and cell polarity, but how their activity is controlled in cells is not well understood. These enzymes are constitutively phosphorylated, insensitive to second messengers, and have relatively low activity. Here we show that protein scaffolds not only localize but also differentially control the catalytic activity of the aPKC PKCζ, thus promoting activity toward localized substrates and restricting activity toward global substrates. Using cellular substrate readouts and scaffolded activity reporters in live cell imaging, we show that PKCζ has highly localized and differentially controlled activity on the scaffolds p62 and Par6. Both scaffolds tether aPKC in an active conformation as assessed through pharmacological inhibition of basal activity, monitored using a genetically encoded reporter for PKC activity. However, binding to Par6 is of higher affinity and is more effective in locking PKCζ in an active conformation. FRET-based translocation assays reveal that insulin promotes the association of both p62 and aPKC with the insulin-regulated scaffold IRS-1. Using the aPKC substrate MARK2 as another readout for activity, we show that overexpression of IRS-1 reduces the phosphorylation of MARK2 and enhances its plasma membrane localization, indicating sequestration of aPKC by IRS-1 away from MARK2. These results are consistent with scaffolds serving as allosteric activators of aPKCs, tethering them in an active conformation near specific substrates. Thus, signaling of these intrinsically low activity kinases is kept at a minimum in the absence of scaffolding interactions, which position the enzymes for stoichiometric phosphorylation of substrates co-localized on the same protein scaffold.
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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.