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Cells Jul 2023A serine/threonine-specific protein kinase B (PKB), also known as Akt, is a key factor in the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway that regulates cell... (Review)
Review
A serine/threonine-specific protein kinase B (PKB), also known as Akt, is a key factor in the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway that regulates cell survival, metabolism and proliferation. Akt phosphorylates many downstream specific substrates, which subsequently control the nuclear envelope breakdown (NEBD), centrosome maturation, spindle assembly, chromosome segregation, and cytokinesis. In vertebrates, Akt is also an important player during oogenesis and preimplantation development. In the signaling pathways regulating mRNA translation, Akt is involved in the control of mammalian target of rapamycin complex 1 (mTORC1) and thereby regulates the activity of a translational repressor, the eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1). In this review, we summarize the functions of Akt in mitosis, meiosis and early embryonic development. Additionally, the role of Akt in the regulation of mRNA translation is addressed with respect to the significance of this process during early development.
Topics: Animals; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Phosphatidylinositol 3-Kinase; Phosphorylation; Phosphoproteins; Signal Transduction; Protein Serine-Threonine Kinases; Oogenesis; Oocytes; Embryonic Development; Mammals
PubMed: 37508495
DOI: 10.3390/cells12141830 -
American Journal of Human Genetics Aug 2023Phosphoinositides (PIs) are membrane phospholipids produced through the local activity of PI kinases and phosphatases that selectively add or remove phosphate groups...
Phosphoinositides (PIs) are membrane phospholipids produced through the local activity of PI kinases and phosphatases that selectively add or remove phosphate groups from the inositol head group. PIs control membrane composition and play key roles in many cellular processes including actin dynamics, endosomal trafficking, autophagy, and nuclear functions. Mutations in phosphatidylinositol 4,5 bisphosphate [PI(4,5)P2] phosphatases cause a broad spectrum of neurodevelopmental disorders such as Lowe and Joubert syndromes and congenital muscular dystrophy with cataracts and intellectual disability, which are thus associated with increased levels of PI(4,5)P2. Here, we describe a neurodevelopmental disorder associated with an increase in the production of PI(4,5)P2 and with PI-signaling dysfunction. We identified three de novo heterozygous missense variants in PIP5K1C, which encodes an isoform of the phosphatidylinositol 4-phosphate 5-kinase (PIP5KIγ), in nine unrelated children exhibiting intellectual disability, developmental delay, acquired microcephaly, seizures, visual abnormalities, and dysmorphic features. We provide evidence that the PIP5K1C variants result in an increase of the endosomal PI(4,5)P2 pool, giving rise to ectopic recruitment of filamentous actin at early endosomes (EEs) that in turn causes dysfunction in EE trafficking. In addition, we generated an in vivo zebrafish model that recapitulates the disorder we describe with developmental defects affecting the forebrain, including the eyes, as well as craniofacial abnormalities, further demonstrating the pathogenic effect of the PIP5K1C variants.
Topics: Animals; Phosphatidylinositols; Syndrome; Actins; Zebrafish; Intellectual Disability; Phosphoric Monoester Hydrolases; Phosphatidylinositol Phosphates
PubMed: 37451268
DOI: 10.1016/j.ajhg.2023.06.012 -
Immunological Medicine Dec 2023Activated phosphatidyl inositol 3-kinase-delta syndrome (APDS) due to gain-of-function variant in the class IA PI3K catalytic subunit p110δ (responsible gene: PIK3CD)... (Review)
Review
Activated phosphatidyl inositol 3-kinase-delta syndrome (APDS) due to gain-of-function variant in the class IA PI3K catalytic subunit p110δ (responsible gene: PIK3CD) was described in 2013. The disease is characterized by recurrent airway infections and bronchiectasis. It is associated with hyper-IgM syndrome due to the defect of immunoglobulin class switch recombination and decreased CD27-positive memory B cells. Patients also suffered from immune dysregulations, such as lymphadenopathy, autoimmune cytopenia or enteropathy. T-cell dysfunction due to increased senescence is associated with a decrease in CD4-positive T lymphocytes and CD45RA-positive naive T lymphocytes, along with increased susceptibility to Epstein-Barr virus/cytomegalovirus infections. In 2014, loss-of-function (LOF) mutation of p85α (responsible gene: PIK3R1), a regulatory subunit of p110δ, was identified as a causative gene, followed in 2016 by the identification of the LOF mutation of PTEN, which dephosphorylates PIP3, leading to the differentiation of APDS1 (PIK3CD-GOF), APDS2 (PIK3R1-LOF) and APDS-L (PTEN-LOF). Since the pathophysiology of patients with APDS varies with a wide range of severity, it is crucial that patients receive appropriate treatment and management. Our research group created a disease outline and a diagnostic flow chart and summarized clinical information such as the severity classification of APDS and treatment options.
Topics: Humans; Immunologic Deficiency Syndromes; Phosphatidylinositol 3-Kinase; Class I Phosphatidylinositol 3-Kinases; Epstein-Barr Virus Infections; Japan; Herpesvirus 4, Human; Phosphatidylinositols
PubMed: 37178059
DOI: 10.1080/25785826.2023.2210366 -
Journal of Cellular Physiology Sep 2023Cell death is a natural biological process that occurs in living organisms. Since 1963, extensive research has shed light on the occurrence, progress, and final outcome... (Review)
Review
Cell death is a natural biological process that occurs in living organisms. Since 1963, extensive research has shed light on the occurrence, progress, and final outcome of cell death. According to different cell phenotypes, it is classified into different types, including apoptosis, pyroptosis, necroptosis, autophagy, ferroptosis, cuproptosis, and so on. However, regardless of the form of cell death, what we ultimately expect is the disappearance of abnormal cells, such as tumor cells, while normal cells survive. As a result, it is vital to investigate the details of cell death, including death triggers, potent regulators, and executioners. Although significant progress has been made in understanding molecular pathways of cell death, many aspects remain unclear because of the complex regulatory networks in cells. Among them, the phosphoinositide-3-kinase (PI3K)/protein kinase B(AKT) pathway is discovered to be a crucial regulator of the cell death process. AKT, as a proto-oncogene, has become a major focus of attention in the medical community due to its role in regulating a multiplicity of cellular functions counting metabolism, immunity, proliferation, survival, transcription, and protein synthesis. Here, we explored the connection between the PI3K/AKT pathway and cell death, aiming to enhance our comprehension of the mechanism underlying this process. Such knowledge may pave the way for the subsequent development of more effective disease treatments, such as finding suitable targets for drug intervention.
Topics: Apoptosis; Cell Proliferation; Phosphatidylinositol 3-Kinase; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Signal Transduction; Humans; Regulated Cell Death
PubMed: 37565518
DOI: 10.1002/jcp.31087 -
International Immunopharmacology Jul 2023Leonurine (Leo) is a natural alkaloid isolated from the herb Leonurus japonicus Houtt. (Leonuri) that has been shown to inhibit oxidative stress and inflammation....
Leonurine (Leo) is a natural alkaloid isolated from the herb Leonurus japonicus Houtt. (Leonuri) that has been shown to inhibit oxidative stress and inflammation. However, the role and mechanism of Leo in acetaminophen (APAP)-induced acute liver injury (ALI) remain unknown. In this study, we investigated the protective effect of Leo against APAP-induced ALI and elucidated the molecular mechanism. Here, we showed that the damage to mouse primary hepatocytes (MPHs) induced by APAP was attenuated by treatment with Leo, which promoted proliferation and inhibited oxidative stress injury, and Leo significantly improved APAP-induced ALI in mice. Leo could protect against APAP-induced ALI by reducing serum aspartate aminotransferase (AST) and alanine transaminase (ALT) levels, hepatic histopathological damage, liver cell necrosis, inflammation, and oxidative stress-induced damage in vivo and in vitro. Moreover, the results indicated that Leo relieved APAP-induced liver cell necrosis by reducing the expression of Bax and cleaved caspase-3 and increasing Bcl-2 expression. Leo alleviated APAP-induced oxidative stress-induced damage by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, which facilitated Nrf2 nuclear translocation and upregulated oxidative stress-related protein expression in liver tissues. Moreover, the results suggested that APAP-induced inflammation in the liver was suppressed by Leo by suppressing the Toll-like receptor 4 (TLR4) and NLR family pyrin domain containing 3 (NLRP3) pathways. In addition, Leo facilitated the activation of the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway in the liver tissue of ALI mice. Network pharmacology, molecular docking, and western blotting showed that PI3K was a potential target of Leo in the treatment of ALI. Molecular docking and cellular thermal shift assay (CETSA) indicated that Leo could stably bind to the PI3K protein. In conclusion, Leo attenuated ALI, and reversed liver cell necrosis, the inflammatory response and oxidative stress-induced damage by regulating the PI3K/AKT signaling pathway.
Topics: Animals; Mice; Acetaminophen; Proto-Oncogene Proteins c-akt; Phosphatidylinositol 3-Kinases; Phosphatidylinositol 3-Kinase; NF-E2-Related Factor 2; Molecular Docking Simulation; Signal Transduction; Liver; Oxidative Stress; Inflammation; Necrosis; Chemical and Drug Induced Liver Injury
PubMed: 37267857
DOI: 10.1016/j.intimp.2023.110375 -
Archives of Biochemistry and Biophysics Jul 2024Phosphatidylinositol 4,5-bisphosphate (PIP), as well as other anionic phospholipids, play a pivotal role in various cellular processes, including ion channel regulation,... (Review)
Review
Phosphatidylinositol 4,5-bisphosphate (PIP), as well as other anionic phospholipids, play a pivotal role in various cellular processes, including ion channel regulation, receptor trafficking, and intracellular signaling pathways. The binding of volatile anesthetics and propofol to PIP leads to alterations in PIP-mediated signaling causing modulation of ion channels such as ɣ-aminobutyric acid type A (GABA) receptors, voltage-gated calcium channels, and potassium channels through various mechanisms. Additionally, the interaction between anionic phospholipids and G protein-coupled receptors plays a critical role in various anesthetic pathways, with these anesthetic-induced changes impacting PIP levels which cause cascading effects on receptor trafficking, including GABA receptor internalization. This comprehensive review of various mechanisms of interaction provides insights into the intricate interplay between PIP signaling and anesthetic-induced changes, shedding light on the molecular mechanisms underlying anesthesia.
Topics: Propofol; Phosphatidylinositol 4,5-Diphosphate; Signal Transduction; Humans; Animals; Anesthetics, Inhalation; Receptors, GABA-A
PubMed: 38801966
DOI: 10.1016/j.abb.2024.110045 -
Autophagy Sep 2023Although PIKFYVE phosphoinositide kinase inhibitors can selectively eliminate PIKFYVE-dependent human cancer cells and , the basis for this selectivity has remained...
Although PIKFYVE phosphoinositide kinase inhibitors can selectively eliminate PIKFYVE-dependent human cancer cells and , the basis for this selectivity has remained elusive. Here we show that the sensitivity of cells to the PIKFYVE inhibitor WX8 is not linked to PIKFYVE expression, macroautophagic/autophagic flux, the BRAF mutation, or ambiguous inhibitor specificity. PIKFYVE dependence results from a deficiency in the PIP5K1C phosphoinositide kinase, an enzyme required for conversion of phosphatidylinositol-4-phosphate (PtdIns4P) into phosphatidylinositol-4,5-bisphosphate (PtdIns[4,5]P/PIP2), a phosphoinositide associated with lysosome homeostasis, endosome trafficking, and autophagy. PtdIns(4,5)P is produced via two independent pathways. One requires PIP5K1C; the other requires PIKFYVE and PIP4K2C to convert PtdIns3P into PtdIns(4,5)P. In PIKFYVE-dependent cells, low concentrations of WX8 specifically inhibit PIKFYVE , thereby increasing the level of its substrate PtdIns3P while suppressing PtdIns(4,5)P synthesis and inhibiting lysosome function and cell proliferation. At higher concentrations, WX8 inhibits both PIKFYVE and PIP4K2C , which amplifies these effects to further disrupt autophagy and induce cell death. WX8 did not alter PtdIns4P levels. Consequently, inhibition of PIP5K1C in WX8-resistant cells transformed them into sensitive cells, and overexpression of PIP5K1C in WX8-sensitive cells increased their resistance to WX8. This discovery suggests that PIKFYVE-dependent cancers could be identified clinically by low levels of PIP5K1C and treated with PIKFYVE inhibitors. DMSO: dimethylsulfoxide; ELISA: enzyme-linked immunosorbent assay; LC3-I: microtubule associated protein light chain 3-I; LC3-II: microtubule associated protein light chain 3-II; MS: mass spectrometry; PtdIns: phosphatidylinositol; PtdIns3P: PtdIns-3-phosphate; PtdIns4P: PtdIns-4-phosphate; PtdIns5P: PtdIns-5-phosphate; PtdIns(3,5)P: PtdIns-3,5-bisphosphate; PtdIns(4,5)P/PIP2: PtdIns-4,5-bisphosphate; PtdIns(3,4,5)P/PIP3: PtdIns-3,4,5-trisphosphate; PIKFYVE: phosphoinositide kinase, FYVE-type zinc finger containing; PIK3C3: phosphatidylinositol 3-kinase catalytic subunit type 3; PI4KA: phosphatidylinositol 4-kinase alpha; PI4KB: phosphatidylinositol 4-kinase beta; PI4K2A: phosphatidylinositol 4-kinase type 2 alpha; PI4K2B: phosphatidylinositol 4-kinase type 2 beta; PIP4K2A: phosphatidylinositol-5-phosphate 4-kinase type 2 alpha; PIP4K2B: phosphatidylinositol-5-phosphate 4-kinase type 2 beta; PIP4K2C: phosphatidylinositol-5-phosphate 4-kinase type 2 gamma; PIP5K1A: phosphatidylinositol-4-phosphate 5-kinase type 1 alpha; PIP5K1B: phosphatidylinositol-4-phosphate 5-kinase type 1 beta; PIP5K1C: phosphatidylinositol-4-phosphate 5-kinase type 1 gamma; WX8: 1H-indole-3-carbaldehyde (4-anilino-6-[4-morpholinyl]-1,3,5-triazin-2-yl)hydrazone.
Topics: Humans; 1-Phosphatidylinositol 4-Kinase; Autophagy; Phosphatidylinositol 3-Kinases; Phosphatidylinositol Phosphates; Phosphatidylinositols; Microtubule-Associated Proteins; Neoplasms; Phosphotransferases (Alcohol Group Acceptor)
PubMed: 36803256
DOI: 10.1080/15548627.2023.2182594 -
Lipids in Health and Disease Apr 2024This study aims to investigate the association between specific lipidomes and the risk of breast cancer (BC) using the Two-Sample Mendelian Randomization (TSMR) approach...
OBJECTIVE
This study aims to investigate the association between specific lipidomes and the risk of breast cancer (BC) using the Two-Sample Mendelian Randomization (TSMR) approach and Bayesian Model Averaging Mendelian Randomization (BMA-MR) method.
METHOD
The study analyzed data from large-scale GWAS datasets of 179 lipidomes to assess the relationship between lipidomes and BC risk across different molecular subtypes. TSMR was employed to explore causal relationships, while the BMA-MR method was carried out to validate the results. The study assessed heterogeneity and horizontal pleiotropy through Cochran's Q, MR-Egger intercept tests, and MR-PRESSO. Moreover, a leave-one-out sensitivity analysis was performed to evaluate the impact of individual single nucleotide polymorphisms on the MR study.
RESULTS
By examining 179 lipidome traits as exposures and BC as the outcome, the study revealed significant causal effects of glycerophospholipids, sphingolipids, and glycerolipids on BC risk. Specifically, for estrogen receptor-positive BC (ER BC), phosphatidylcholine (P < 0.05) and phosphatidylinositol (OR: 0.916-0.966, P < 0.05) within glycerophospholipids play significant roles, along with the importance of glycerolipids (diacylglycerol (OR = 0.923, P < 0.001) and triacylglycerol, OR: 0.894-0.960, P < 0.05)). However, the study did not observe a noteworthy impact of sphingolipids on ERBC. In the case of estrogen receptor-negative BC (ER BC), not only glycerophospholipids, sphingolipids (OR = 1.085, P = 0.008), and glycerolipids (OR = 0.909, P = 0.002) exerted an influence, but the protective effect of sterols (OR: 1.034-1.056, P < 0.05) was also discovered. The prominence of glycerolipids was minimal in ER-BC. Phosphatidylethanolamine (OR: 1.091-1.119, P < 0.05) was an important causal effect in ERBC.
CONCLUSIONS
The findings reveal that phosphatidylinositol and triglycerides levels decreased the risk of BC, indicating a potential protective role of these lipid molecules. Moreover, the study elucidates BC's intricate lipid metabolic pathways, highlighting diverse lipidome structural variations that may have varying effects in different molecular subtypes.
Topics: Bayes Theorem; Lipidomics; Mendelian Randomization Analysis; Glycerophospholipids; Phosphatidylinositols; Sphingolipids; Receptors, Estrogen; Genome-Wide Association Study; Neoplasms
PubMed: 38622701
DOI: 10.1186/s12944-024-02103-2 -
Journal of Translational Medicine Jan 2024Breast cancer (BC) is a multifaceted disease characterized by distinct molecular subtypes and varying responses to treatment. In BC, the phosphatidylinositol 3-kinase... (Review)
Review
Breast cancer (BC) is a multifaceted disease characterized by distinct molecular subtypes and varying responses to treatment. In BC, the phosphatidylinositol 3-kinase (PI3K) pathway has emerged as a crucial contributor to the development, advancement, and resistance to treatment. This review article explores the implications of the PI3K pathway in predictive, preventive, and personalized medicine for BC. It emphasizes the identification of predictive biomarkers, such as PIK3CA mutations, and the utility of molecular profiling in guiding treatment decisions. The review also discusses the potential of targeting the PI3K pathway for preventive strategies and the customization of therapy based on tumor stage, molecular subtypes, and genetic alterations. Overcoming resistance to PI3K inhibitors and exploring combination therapies are addressed as important considerations. While this field holds promise in improving patient outcomes, further research and clinical trials are needed to validate these approaches and translate them into clinical practice.
Topics: Humans; Female; Phosphatidylinositol 3-Kinase; Phosphatidylinositol 3-Kinases; Breast Neoplasms; Precision Medicine; Phosphoinositide-3 Kinase Inhibitors; Mutation; Class I Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt
PubMed: 38172946
DOI: 10.1186/s12967-023-04841-w -
The Journal of Cell Biology Sep 2023The lipid phosphatidylinositol 3,5-bisphosphate-PI(3,5)P2-is known to be a key regulator of cellular traffic in health and disease, but its cellular localization was...
The lipid phosphatidylinositol 3,5-bisphosphate-PI(3,5)P2-is known to be a key regulator of cellular traffic in health and disease, but its cellular localization was somewhat enigmatic until now, with the discovery of a new PI(3,5)P2 biosensor reported in this issue of JCB by Vines et al. (2023. J. Cell Biol.https://doi.org/10.1083/jcb.202209077).
Topics: Phosphatidylinositol Phosphates; Phosphatidylinositols; Biosensing Techniques
PubMed: 37578524
DOI: 10.1083/jcb.202308004