bims-micesi Biomed News
on Mitotic cell signalling
Issue of 2022–05–08
sixteen papers selected by
Valentina Piano, Max Planck Institute of Molecular Physiology
  1. [Photopharmacological Tools for Mitotic Cell Division].
  2. Potent microtubule depolymerizing activity of a mitotic Kif18b-MCAK-EB network.
  3. Motor Cooperation During Mitosis and Ciliogenesis.
  4. Mitotic kinase oscillation governs the latching of cell cycle switches.
  5. BUBs Are New Biomarkers of Promoting Tumorigenesis and Affecting Prognosis in Breast Cancer.
  6. CDC20 in and out of mitosis: a prognostic factor and therapeutic target in hematological malignancies.
  7. Centrioles generate a local pulse of Polo/PLK1 activity to initiate mitotic centrosome assembly.
  8. Nonlinear mechanics of human mitotic chromosomes.
  9. Cell cycle-specific phase separation regulated by protein charge blockiness.
  10. Mechanical regulation of cell-cycle progression and division.
  11. Stable inheritance of H3.3-containing nucleosomes during mitotic cell divisions.
  12. Mad3 modulates the G1 Cdk and acts as a timer in the Start network.
  13. Biochemical and crystallization analysis of the CENP-SX-DNA complex.
  14. Tubulinopathy mutations in TUBA1A that disrupt neuronal morphogenesis and migration override XMAP215/Stu2 regulation of microtubule dynamics.
  15. Meet the authors: Florian Chardon, Aleksandre Japaridze, and Daniele Fachinetti.
  16. Protein Kinase C Life Cycle: Explained Through Systems Biology Approach.
  1. Yakugaku Zasshi. 2022 ;142(5): 513-519
    [Photopharmacological Tools for Mitotic Cell Division].
    Kazuya Matsuo.
      Genetic information is replicated and transmitted from a parent cell to two identical daughter cells through mitotic cell division. To accomplish this dynamic process with high accuracy and precision, various motor proteins work in a concerted manner. Especially in the metaphase, mitotic chromosomes are delivered by the motor protein of centromere-associated protein E (CENP-E) to the cell equatorial plane (metaphase plate) along mitotic spindles. However, the critical functional failure of CENP-E can activate the spindle assembly checkpoint through the misalignment of chromosomes at the metaphase plate. In this symposium review, the reversibly photoswitchable CENP-E inhibitor PCEI-HU (5) is reported. Compound 5 exhibited almost quantitative trans-cis photoisomerization of the arylazopyrazole photoswitch by illuminating light at 365 nm and 510 nm. Depending on the photoisomerization, CENP-E activity was regulated not only in vitro but also in cells. We successfully established a novel technique using 5 to dynamically photocontrol the CENP-E-dependent chromosome movement and mitotic progression in a living cell.
    Keywords:  azobenzene; centromere-associated protein E (CENP-E); chromosome; photoisomerization; photoswitchable inhibitor
    DOI:  https://doi.org/10.1248/yakushi.21-00203-5
  2. J Cell Sci. 2022 May 03. pii: jcs.260144. [Epub ahead of print]
    Potent microtubule depolymerizing activity of a mitotic Kif18b-MCAK-EB network.
    Toni McHugh, Julie P I Welburn.
      The precise regulation of microtubule length during mitosis is essential to assemble and position the mitotic spindle and segregate chromosomes. The kinesin-13 Kif2C/MCAK acts as a potent microtubule depolymerase diffusing short distances on microtubules, while the kinesin-8 Kif18b is a processive motor with weak depolymerase activity. However, the individual activities of these factors cannot explain the dramatic increase in microtubule dynamics in mitosis. Using in vitro reconstitution and single molecule imaging, we demonstrate that Kif18b, MCAK and the plus-end tracking protein EB3 act in an integrated manner to potently promote microtubule depolymerization at very low concentration. We find that Kif18b can transport EB3 and MCAK and promotes their accumulation to microtubule plus ends through multivalent weak interactions. Together, our work defines the mechanistic basis for a cooperative Kif18b-EB-MCAK network at microtubule plus ends, that acts to efficiently shorten and regulate microtubules in mitosis, essential for correct chromosome segregation.
    Keywords:  Depolymerization; Kinesin; Microtubule; Mitosis; Regulation
    DOI:  https://doi.org/10.1242/jcs.260144
  3. Annu Rev Cell Dev Biol. 2022 May 05.
    Motor Cooperation During Mitosis and Ciliogenesis.
    Guangshuo Ou, Jonathan M Scholey.
      Cilia and mitotic spindles are microtubule (MT)-based, macromolecular machines that consecutively assemble and disassemble during interphase and M phase of the cell cycle, respectively, and play fundamental roles in how eukaryotic cells swim through a fluid, sense their environment, and divide to reproduce themselves. The formation and function of these structures depend on several types of cytoskeletal motors, notably MT-based kinesins and dyneins, supplemented by actin-based myosins, which may function independently or collaboratively during specific steps in the pathway of mitosis or ciliogenesis. System-specific differences in these pathways occur because, instead of conforming to a simple one motor-one function rule, ciliary and mitotic motors can be deployed differently by different cell types. This reflects the well-known influence of natural selection on basic molecular processes, creating diversity at subcellular scales. Here we review our current understanding of motor function and cooperation during the assembly-disassembly, maintenance, and functions of cilia and mitotic spindles. Expected final online publication date for the Annual Review of Cell and Developmental Biology Volume 38 is October 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
    DOI:  https://doi.org/10.1146/annurev-cellbio-121420-100107
  4. Curr Biol. 2022 Apr 26. pii: S0960-9822(22)00585-1. [Epub ahead of print]
    Mitotic kinase oscillation governs the latching of cell cycle switches.
    Bela Novak, John J Tyson.
      In 1996, Kim Nasmyth1 proposed that the eukaryotic cell cycle is an alternating sequence of transitions from G1 to S-G2-M and back again. These two phases correlate to high activity of cyclin-dependent kinases (CDKs) that trigger S-G2-M events and CDK antagonists that stabilize G1 phase. We associated these "alternative phases" with the coexistence of two stable steady states of the biochemical reactions among CDKs and their antagonists.2,3 Transitions between these steady states (G1-to-S and M-to-G1) are driven by "helper" proteins. The fact that the transitions are irreversible is guaranteed by a "latching" property of the molecular switches, as we have argued in previous publications.4,5 Here, we show that if the latch is broken, then the biochemical reactions can swing back-and-forth across the transitions; either G1-S-G1-S … (periodic DNA replication without mitosis or cell division) or M-(G1)-M-(G1) … (periodic Cdc14 release, without fully exiting mitosis). Using mathematical modeling of the molecular control circuit in budding yeast, we provide a fresh account of aberrant cell cycles in mutant strains: endoreplication in the clb1-5Δ strain6 and periodic release and resequestration of Cdc14 (an "exit" phosphatase) in the CLB2kdΔ strain.7,8 In our opinion, these "endocycles" are not autonomous oscillatory modules that must be entrained by the CDK oscillator6,7 but rather inadvertent and deleterious oscillations that are normally suppressed by the CDK latching-gate mechanism.8.
    Keywords:  Cdc14 endocycles; bistability; cell cycle; checkpoints; cyclin-dependent kinase; endoreplication cycles; mathematical model
    DOI:  https://doi.org/10.1016/j.cub.2022.04.016
  5. Dis Markers. 2022 ;2022 2760432
    BUBs Are New Biomarkers of Promoting Tumorigenesis and Affecting Prognosis in Breast Cancer.
    Shunan Wang, Xinyu Liu, Meng Yang, Dongqi Yuan, Kui Ye, Xin Qu, Xinchao Wang.
       Background: A tumor occurs because of abnormal cell multiplication caused by many variables like a significant disturbance in the regulation of cell growth and the instability of chromosome mitosis. Budding uninhibited by benzimidazoles 1 (BUB1), BUB1 mitotic checkpoint serine/threonine kinase B (BUB1B), and budding uninhibited by benzimidazoles 3 (BUB3) are key regulators of mitosis, and their abnormal expression is highly correlated with breast cancer (BrCa), sarcoma, hepatic carcinoma, and other malignant tumors. However, the occurrence of BUBs (BUB1, BUB1B, and BUB3) and the development of BrCa have not been systematically explained.
    Methods: Find out the target gene by looking up literature on PubMed and CNKI. Using the R software, TCGA, GEO, Kaplan-Meier Plotter, TIMER, and other databases, we studied the level of transcription, genetic changes, and physiological functions of BUBs in BrCa patients and their relationship with the origin, development, prognosis, immunity, and drug resistance of BrCa patients. Findings. We found that the high expression level of BUBs in BrCa tissues proposed a poor prognosis. The multivariate Cox regression analysis suggested that BUB1B and BUB3 might be independent prognostic factors of BrCa. In addition, the Metascape functional enrichment analysis showed that BUBs may be involved in the composition of the spindle, chromosome, and other structures and play a role in mitosis, sister chromatid separation, and other processes. Pathway enrichment suggests that BUBs may affect the cell cycle and lead to abnormal proliferation. Meanwhile, we also found that BUB3 can negatively regulate B lymphocytes, and BUB1 and BUB1B inhibit immune responses by promoting the secretion level of checkpoint molecules of the immune system, leading to immune escape of tumor cells.
    Conclusion: We speculate that BUB1, BUB1B, and BUB3 may be therapeutic targets for BrCa patients and also provide new therapeutic strategies for BrCa treatment.
    DOI:  https://doi.org/10.1155/2022/2760432
  6. J Exp Clin Cancer Res. 2022 Apr 30. 41(1): 159
    CDC20 in and out of mitosis: a prognostic factor and therapeutic target in hematological malignancies.
    Samantha Bruno, Andrea Ghelli Luserna di Rorà, Roberta Napolitano, Simona Soverini, Giovanni Martinelli, Giorgia Simonetti.
      Cell division cycle 20 homologue (CDC20) is a well-known regulator of cell cycle, as it controls the correct segregation of chromosomes during mitosis. Many studies have focused on the biological role of CDC20 in cancer development, as alterations of its functionality have been linked to genomic instability and evidence demonstrated that high CDC20 expression levels are associated with poor overall survival in solid cancers. More recently, novel CDC20 functions have been demonstrated or suggested, including the regulation of apoptosis and stemness properties and a correlation with immune cell infiltration. Here, we here summarize and discuss the role of CDC20 inside and outside mitosis, starting from its network of interacting proteins. In the last years, CDC20 has also attracted more interest in the blood cancer field, being overexpressed and showing an association with prognosis both in myeloid and lymphoid malignancies. Preclinical findings showed that selective CDC20 and APC/CCDC20/APC/CCDH1 inhibitors, namely Apcin and proTAME, are effective against lymphoma and multiple myeloma cells, resulting in mitotic arrest and apoptosis and synergizing with clinically-relevant drugs. The evidence and hypothesis presented in this review provide the input for further biological and chemical studies aiming to dissect novel potential CDC20 roles and targeting strategies in hematological malignancies.
    Keywords:  Apcin; CDC20; Hematological malignancies; Mitotic checkpoint
    DOI:  https://doi.org/10.1186/s13046-022-02363-9
  7. EMBO J. 2022 May 03. e110891
    Centrioles generate a local pulse of Polo/PLK1 activity to initiate mitotic centrosome assembly.
    Siu-Shing Wong, Zachary M Wilmott, Saroj Saurya, Ines Alvarez-Rodrigo, Felix Y Zhou, Kwai-Yin Chau, Alain Goriely, Jordan W Raff.
      Mitotic centrosomes are formed when centrioles start to recruit large amounts of pericentriolar material (PCM) around themselves in preparation for mitosis. This centrosome "maturation" requires the centrioles and also Polo/PLK1 protein kinase. The PCM comprises several hundred proteins and, in Drosophila, Polo cooperates with the conserved centrosome proteins Spd-2/CEP192 and Cnn/CDK5RAP2 to assemble a PCM scaffold around the mother centriole that then recruits other PCM client proteins. We show here that in Drosophila syncytial blastoderm embryos, centrosomal Polo levels rise and fall during the assembly process-peaking, and then starting to decline, even as levels of the PCM scaffold continue to rise and plateau. Experiments and mathematical modelling indicate that a centriolar pulse of Polo activity, potentially generated by the interaction between Polo and its centriole receptor Ana1 (CEP295 in humans), could explain these unexpected scaffold assembly dynamics. We propose that centrioles generate a local pulse of Polo activity prior to mitotic entry to initiate centrosome maturation, explaining why centrioles and Polo/PLK1 are normally essential for this process.
    Keywords:  PCM; PLK1; cell cycle; centrosome; oscillator
    DOI:  https://doi.org/10.15252/embj.2022110891
  8. Nature. 2022 May 04.
    Nonlinear mechanics of human mitotic chromosomes.
    Anna E C Meijering, Kata Sarlós, Christian F Nielsen, Hannes Witt, Janni Harju, Emma Kerklingh, Guus H Haasnoot, Anna H Bizard, Iddo Heller, Chase P Broedersz, Ying Liu, Erwin J G Peterman, Ian D Hickson, Gijs J L Wuite.
      In preparation for mitotic cell division, the nuclear DNA of human cells is compacted into individualized, X-shaped chromosomes1. This metamorphosis is driven mainly by the combined action of condensins and topoisomerase IIα (TOP2A)2,3, and has been observed using microscopy for over a century. Nevertheless, very little is known about the structural organization of a mitotic chromosome. Here we introduce a workflow to interrogate the organization of human chromosomes based on optical trapping and manipulation. This allows high-resolution force measurements and fluorescence visualization of native metaphase chromosomes to be conducted under tightly controlled experimental conditions. We have used this method to extensively characterize chromosome mechanics and structure. Notably, we find that under increasing mechanical load, chromosomes exhibit nonlinear stiffening behaviour, distinct from that predicted by classical polymer models4. To explain this anomalous stiffening, we introduce a hierarchical worm-like chain model that describes the chromosome as a heterogeneous assembly of nonlinear worm-like chains. Moreover, through inducible degradation of TOP2A5 specifically in mitosis, we provide evidence that TOP2A has a role in the preservation of chromosome compaction. The methods described here open the door to a wide array of investigations into the structure and dynamics of both normal and disease-associated chromosomes.
    DOI:  https://doi.org/10.1038/s41586-022-04666-5
  9. Nat Cell Biol. 2022 May 05.
    Cell cycle-specific phase separation regulated by protein charge blockiness.
    Hiroya Yamazaki, Masatoshi Takagi, Hidetaka Kosako, Tatsuya Hirano, Shige H Yoshimura.
      Dynamic morphological changes of intracellular organelles are often regulated by protein phosphorylation or dephosphorylation1-6. Phosphorylation modulates stereospecific interactions among structured proteins, but how it controls molecular interactions among unstructured proteins and regulates their macroscopic behaviours remains unknown. Here we determined the cell cycle-specific behaviour of Ki-67, which localizes to the nucleoli during interphase and relocates to the chromosome periphery during mitosis. Mitotic hyperphosphorylation of disordered repeat domains of Ki-67 generates alternating charge blocks in these domains and increases their propensity for liquid-liquid phase separation (LLPS). A phosphomimetic sequence and the sequences with enhanced charge blockiness underwent strong LLPS in vitro and induced chromosome periphery formation in vivo. Conversely, mitotic hyperphosphorylation of NPM1 diminished a charge block and suppressed LLPS, resulting in nucleolar dissolution. Cell cycle-specific phase separation can be modulated via phosphorylation by enhancing or reducing the charge blockiness of disordered regions, rather than by attaching phosphate groups to specific sites.
    DOI:  https://doi.org/10.1038/s41556-022-00903-1
  10. Trends Cell Biol. 2022 Apr 28. pii: S0962-8924(22)00082-4. [Epub ahead of print]
    Mechanical regulation of cell-cycle progression and division.
    Vivek K Gupta, Ovijit Chaudhuri.
      Cell-cycle progression and division are fundamental biological processes in animal cells, and their biochemical regulation has been extensively studied. An emerging body of work has revealed how mechanical interactions of cells with their microenvironment in tissues, including with the extracellular matrix (ECM) and neighboring cells, also plays a crucial role in regulating cell-cycle progression and division. We review recent work on how cells interpret physical cues and alter their mechanics to promote cell-cycle progression and initiate cell division, and then on how dividing cells generate forces on their surrounding microenvironment to successfully divide. Finally, the article ends by discussing how force generation during division potentially contributes to larger tissue-scale processes involved in development and homeostasis.
    Keywords:  cell cycle; cell division; extracellular matrix; force generation; mechanotransduction; microenvironment; mitosis
    DOI:  https://doi.org/10.1016/j.tcb.2022.03.010
  11. Nat Commun. 2022 May 06. 13(1): 2514
    Stable inheritance of H3.3-containing nucleosomes during mitotic cell divisions.
    Xiaowei Xu, Shoufu Duan, Xu Hua, Zhiming Li, Richard He, Zhiguo Zhaang.
      Newly synthesized H3.1 and H3.3 histones are assembled into nucleosomes by different histone chaperones in replication-coupled and replication-independent pathways, respectively. However, it is not clear how parental H3.3 molecules are transferred following DNA replication, especially when compared to H3.1. Here, by monitoring parental H3.1- and H3.3-SNAP signals, we show that parental H3.3, like H3.1, are stably transferred into daughter cells. Moreover, Mcm2-Pola1 and Pole3-Pole4, two pathways involved in parental histone transfer based upon the analysis of modifications on parental histones, participate in the transfer of both H3.1 and H3.3 following DNA replication. Lastly, we found that Mcm2, Pole3 and Pole4 mutants defective in parental histone transfer show defects in chromosome segregation. These results indicate that in contrast to deposition of newly synthesized H3.1 and H3.3, transfer of parental H3.1 and H3.3 is mediated by these shared mechanisms, which contributes to epigenetic memory of gene expression and maintenance of genome stability.
    DOI:  https://doi.org/10.1038/s41467-022-30298-4
  12. Sci Adv. 2022 May 06. 8(18): eabm4086
    Mad3 modulates the G1 Cdk and acts as a timer in the Start network.
    Alexis P Pérez, Marta H Artés, David F Moreno, Josep Clotet, Martí Aldea.
      Cells maintain their size within limits over successive generations to maximize fitness and survival. Sizer, timer, and adder behaviors have been proposed as possible alternatives to coordinate growth and cell cycle progression. Regarding budding yeast cells, a sizer mechanism is thought to rule cell cycle entry at Start. However, while many proteins controlling the size of these cells have been identified, the mechanistic framework in which they participate to achieve cell size homeostasis is not understood. We show here that intertwined APC and SCF degradation machineries with specific adaptor proteins drive cyclic accumulation of the G1 Cdk in the nucleus, reaching maximal levels at Start. The mechanism incorporates Mad3, a centromeric-signaling protein that subordinates G1 progression to the previous mitosis as a memory factor. This alternating-degradation device displays the properties of a timer and, together with the sizer device, would constitute a key determinant of cell cycle entry.
    DOI:  https://doi.org/10.1126/sciadv.abm4086
  13. Acta Crystallogr F Struct Biol Commun. 2022 May 01. 78(Pt 5): 193-199
    Biochemical and crystallization analysis of the CENP-SX-DNA complex.
    Sho Ito, Tatsuya Nishino.
      The CENP-SX (MHF) complex is a conserved histone-fold protein complex that is involved in chromosome segregation and DNA repair. It can bind to DNA on its own as well as in complex with other proteins such as CENP-TW and FANCM to recognize specific substrates. CENP-SX binds nonspecifically to dsDNA, similar to other histone-fold proteins. Several low-resolution structures of CENP-SX in complex with DNA are known, but a high-resolution structure is still lacking. The DNA-binding properties of CENP-SX and FANCM-CENP-SX complexes with various lengths of dsDNA were compared and the band-shift patterns and migration positions were found to differ. To confirm the DNA-binding properties in detail, CENP-SX-DNA and FANCM-CENP-SX-DNA complexes were crystallized. Analysis of the crystals revealed that they all contained the CENP-SX-DNA complex, irrespective of the complex that was used in crystallization. Detailed diffraction data analyses revealed that there were two types of crystal with different space groups, P21 and C2, where the volume of the P21 asymmetric unit is twice as large as that of the C2 asymmetric unit. Analysis of the self-rotation function revealed the presence of twofold and fourfold symmetry in both crystals. This suggests that there may be multiple molecules of CENP-SX and DNA within the asymmetric unit with respective symmetry. Structure determination of the present crystals should reveal details of the DNA-binding properties of CENP-SX.
    Keywords:  CENP-SX–DNA complex; DNA repair; chromosome segregation; crystallization; histone-fold complexes; protein–DNA interactions
    DOI:  https://doi.org/10.1107/S2053230X22003843
  14. Elife. 2022 May 05. pii: e76189. [Epub ahead of print]11
    Tubulinopathy mutations in TUBA1A that disrupt neuronal morphogenesis and migration override XMAP215/Stu2 regulation of microtubule dynamics.
    Katelyn J Hoff, Jayne E Aiken, Mark A Gutierrez, Santos J Franco, Jeffrey K Moore.
      Heterozygous, missense mutations in a- or b-tubulin genes are associated with a wide range of human brain malformations, known as tubulinopathies. We seek to understand whether a mutation's impact at the molecular and cellular levels scale with the severity of brain malformation. Here we focus on two mutations at the valine 409 residue of TUBA1A, V409I and V409A, identified in patients with pachygyria or lissencephaly, respectively. We find that ectopic expression of TUBA1A-V409I/A mutants disrupt neuronal migration in mice and promote excessive neurite branching and a decrease in the number of neurite retraction events in primary rat neuronal cultures. These neuronal phenotypes are accompanied by increased microtubule acetylation and polymerization rates. To determine the molecular mechanisms, we modeled the V409I/A mutants in budding yeast and found that they promote intrinsically faster microtubule polymerization rates in cells and in reconstitution experiments with purified tubulin. In addition, V409I/A mutants decrease the recruitment of XMAP215/Stu2 to plus ends in budding yeast and ablate tubulin binding to TOG domains. In each assay tested, the TUBA1A-V409I mutant exhibits an intermediate phenotype between wild type and the more severe TUBA1A-V409A, reflecting the severity observed in brain malformations. Together, our data support a model in which the V409I/A mutations disrupt microtubule regulation typically conferred by XMAP215 proteins during neuronal morphogenesis and migration, and this impact on tubulin activity at the molecular level scales with the impact at the cellular and tissue levels.
    Keywords:  S. cerevisiae; cell biology; developmental biology; mouse; rat
    DOI:  https://doi.org/10.7554/eLife.76189
  15. Mol Cell. 2022 May 05. pii: S1097-2765(22)00267-2. [Epub ahead of print]82(9): 1605-1607
    Meet the authors: Florian Chardon, Aleksandre Japaridze, and Daniele Fachinetti.
      We talk to first authors Florian Chardon and Aleksandre Japaridze as well as corresponding author Daniele Fachinetti about their paper "CENP-B-mediated DNA loops regulate activity and stability of human centromeres," their journeys from France, Georgia and Italy, how their collaboration was established on a conference bus ride, how they celebrated acceptance, and the importance of celebration!
    DOI:  https://doi.org/10.1016/j.molcel.2022.03.029
  16. Front Physiol. 2022 ;13 818688
    Protein Kinase C Life Cycle: Explained Through Systems Biology Approach.
    Naveed Aslam, Farah Alvi.
      Protein kinase C (PKC) enzymes are a family of kinases that mediate signal transduction originating at the cell surface. Most cell membranes can contain functional PKC enzymes. Aberrations in the PKC life cycle may result in cellular damage and dysfunction. For example, some cancerous cells exhibit alterations in PKC activity. Here, we use a systems biology approach to describe a molecular model of the PKC life cycle. Understanding the PKC life cycle is necessary to identify new drug targets. The PKC life cycle is composed of three key regulatory processes: maturation, activation, and termination. These processes precisely control PKC enzyme levels. This model describes the fate of PKC during de novo synthesis and PKC's lipid-mediated activation cycle. We utilize a systems biology approach to show the PKC life cycle is controlled by multiple phosphorylation and dephosphorylation events. PKC processing events can be divided into two types: maturation via processing of newly synthesized enzyme and secondary messenger-dependent activation of dormant, but catalytically competent enzyme. Newly synthesized PKC enzyme is constitutively processed through three ordered phosphorylations and stored in the cytosol as a stable, signaling-competent inactive and autoinhibited molecule. Upon extracellular stimulation, diacylglycerol (DAG) and calcium ion (Ca2+) generated at the membrane bind PKC. PKC then undergoes cytosol-to-membrane translocation and subsequent activation. Our model shows that, once activated, PKC is prone to dephosphorylation and subsequent degradation. This model also describes the role of HSP70 in stabilization and re-phosphorylation of dephosphorylated PKC, replenishing the PKC pool. Our model shows how the PKC pool responds to different intensities of extracellular stimuli? We show that blocking PHLPP dephosphorylation replenishes the PKC pool in a dose-dependent manner. This model provides a comprehensive understanding of PKC life cycle regulation.
    Keywords:  PKC; activation; down-regulation; life cycle; lipid
    DOI:  https://doi.org/10.3389/fphys.2022.818688
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