ArticleThe Biochemical journal2016
Protein kinase Cζ exhibits constitutive phosphorylation and phosphatidylinositol-3,4,5-triphosphate-independent regulation.
Article in The Biochemical journal, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 39 citations in OpenAlex.
- mTOR signaling governs the formation of epithelial apical projections via S6K1-RhoA and aPKC-Lgl2 axes.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- A PKCη missense mutation enhances Golgi-localized signaling and is associated with recessively inherited familial Alzheimer's disease.Science signaling · 2025Article
- Protein kinase C eta enhances Golgi-localized signaling and is associated with Alzheimer's disease using a recessive mode of inheritance.medRxiv : the preprint server for health sciences · 2025Article
- Intracellular Sphingosine-1-Phosphate Induces Lipolysis Through Direct Activation of Protein Kinase C Zeta.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2025Article
- Into the fold: advances in understanding aPKC membrane dynamics.The Biochemical journal · 2023Article
- A novel non‑selective atypical PKC agonist could protect neuronal cell line from Aβ‑oligomer induced toxicity by suppressing Aβ generation.Molecular medicine reports · 2022Article
- mTOR Regulation of AGC Kinases: New Twist to an Old Tail.Molecular pharmacology · 2022Review
- MTOR promotes basal cell carcinoma growth through atypical PKC.Experimental dermatology · 2021Article
- Identification of Key Phospholipids That Bind and Activate Atypical PKCs.Biomedicines · 2021Article
- Role of Protein Kinase C in Immune Cell Activation and Its Implication Chemical-Induced Immunotoxicity.Advances in experimental medicine and biology · 2021Article
- mTORC2 Is Involved in the Induction of RSK Phosphorylation by Serum or Nutrient Starvation.Cells · 2020Article
- Glucocorticoids and myosin5b loss of function induce heightened PKA signaling in addition to membrane traffic defects.Molecular biology of the cell · 2019Article
- aPKC in neuronal differentiation, maturation and function.Neuronal signaling · 2019Review
- 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
- mTORC2 modulates the amplitude and duration of GFAT1 Ser-243 phosphorylation to maintain flux through the hexosamine pathway during starvation.The Journal of biological chemistry · 2018Article
- Actin polymerization controls cilia-mediated signaling.The Journal of cell biology · 2018Article
- Protein kinase Cα gain-of-function variant in Alzheimer's disease displays enhanced catalysis by a mechanism that evades down-regulation.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- Protein kinase C: perfectly balanced.Critical reviews in biochemistry and molecular biology · 2018Review
- Short-term heat stress altered metabolism and insulin signaling in skeletal muscle.Journal of animal science · 2018Article
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
Abstract
Atypical protein kinase C (aPKC) isoenzymes are key modulators of insulin signalling, and their dysfunction correlates with insulin-resistant states in both mice and humans. Despite the engaged interest in the importance of aPKCs to type 2 diabetes, much less is known about the molecular mechanisms that govern their cellular functions than for the conventional and novel PKC isoenzymes and the functionally-related protein kinase B (Akt) family of kinases. Here we show that aPKC is constitutively phosphorylated and, using a genetically-encoded reporter for PKC activity, basally active in cells. Specifically, we show that phosphorylation at two key regulatory sites, the activation loop and turn motif, of the aPKC PKCζ in multiple cultured cell types is constitutive and independently regulated by separate kinases: ribosome-associated mammalian target of rapamycin complex 2 (mTORC2) mediates co-translational phosphorylation of the turn motif, followed by phosphorylation at the activation loop by phosphoinositide-dependent kinase-1 (PDK1). Live cell imaging reveals that global aPKC activity is constitutive and insulin unresponsive, in marked contrast to the insulin-dependent activation of Akt monitored by an Akt-specific reporter. Nor does forced recruitment to phosphoinositides by fusing the pleckstrin homology (PH) domain of Akt to the kinase domain of PKCζ alter either the phosphorylation or activity of PKCζ. Thus, insulin stimulation does not activate PKCζ through the canonical phosphatidylinositol-3,4,5-triphosphate-mediated pathway that activates Akt, contrasting with previous literature on PKCζ activation. These studies support a model wherein an alternative mechanism regulates PKCζ-mediated insulin signalling that does not utilize conventional activation via agonist-evoked phosphorylation at the activation loop. Rather, we propose that scaffolding near substrates drives the function of PKCζ.
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Registered trials
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