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Cancer Communications (London, England) Oct 2022Breast cancer is the most common cancer worldwide. The occurrence of breast cancer is associated with many risk factors, including genetic and hereditary predisposition.... (Review)
Review
Breast cancer is the most common cancer worldwide. The occurrence of breast cancer is associated with many risk factors, including genetic and hereditary predisposition. Breast cancers are highly heterogeneous. Treatment strategies for breast cancer vary by molecular features, including activation of human epidermal growth factor receptor 2 (HER2), hormonal receptors (estrogen receptor [ER] and progesterone receptor [PR]), gene mutations (e.g., mutations of breast cancer 1/2 [BRCA1/2] and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [PIK3CA]) and markers of the immune microenvironment (e.g., tumor-infiltrating lymphocyte [TIL] and programmed death-ligand 1 [PD-L1]). Early-stage breast cancer is considered curable, for which local-regional therapies (surgery and radiotherapy) are the cornerstone, with systemic therapy given before or after surgery when necessary. Preoperative or neoadjuvant therapy, including targeted drugs or immune checkpoint inhibitors, has become the standard of care for most early-stage HER2-positive and triple-negative breast cancer, followed by risk-adapted post-surgical strategies. For ER-positive early breast cancer, endocrine therapy for 5-10 years is essential. Advanced breast cancer with distant metastases is currently considered incurable. Systemic therapies in this setting include endocrine therapy with targeted agents, such as CDK4/6 inhibitors and phosphoinositide 3-kinase (PI3K) inhibitors for hormone receptor-positive disease, anti-HER2 targeted therapy for HER2-positive disease, poly(ADP-ribose) polymerase inhibitors for BRCA1/2 mutation carriers and immunotherapy currently for part of triple-negative disease. Innovation technologies of precision medicine may guide individualized treatment escalation or de-escalation in the future. In this review, we summarized the latest scientific information and discussed the future perspectives on breast cancer.
Topics: B7-H1 Antigen; Class I Phosphatidylinositol 3-Kinases; Humans; Immune Checkpoint Inhibitors; Phosphatidylinositol 3-Kinases; Phosphatidylinositols; Poly(ADP-ribose) Polymerase Inhibitors; Receptors, Estrogen; Receptors, Progesterone; Triple Negative Breast Neoplasms; Tumor Microenvironment
PubMed: 36074908
DOI: 10.1002/cac2.12358 -
Nature Reviews. Molecular Cell Biology Dec 2022Phosphoinositides are signalling lipids derived from phosphatidylinositol, a ubiquitous phospholipid in the cytoplasmic leaflet of eukaryotic membranes. Initially... (Review)
Review
Phosphoinositides are signalling lipids derived from phosphatidylinositol, a ubiquitous phospholipid in the cytoplasmic leaflet of eukaryotic membranes. Initially discovered for their roles in cell signalling, phosphoinositides are now widely recognized as key integrators of membrane dynamics that broadly impact on all aspects of cell physiology and on disease. The past decade has witnessed a vast expansion of our knowledge of phosphoinositide biology. On the endocytic and exocytic routes, phosphoinositides direct the inward and outward flow of membrane as vesicular traffic is coupled to the conversion of phosphoinositides. Moreover, recent findings on the roles of phosphoinositides in autophagy and the endolysosomal system challenge our view of lysosome biology. The non-vesicular exchange of lipids, ions and metabolites at membrane contact sites in between organelles has also been found to depend on phosphoinositides. Here we review our current understanding of how phosphoinositides shape and direct membrane dynamics to impact on cell physiology, and provide an overview of emerging concepts in phosphoinositide regulation.
Topics: Phosphatidylinositols; Cell Membrane; Endosomes; Signal Transduction; Lysosomes
PubMed: 35589852
DOI: 10.1038/s41580-022-00490-x -
Nature Sep 2022Lysosomal dysfunction has been increasingly linked to disease and normal ageing. Lysosomal membrane permeabilization (LMP), a hallmark of lysosome-related diseases, can...
Lysosomal dysfunction has been increasingly linked to disease and normal ageing. Lysosomal membrane permeabilization (LMP), a hallmark of lysosome-related diseases, can be triggered by diverse cellular stressors. Given the damaging contents of lysosomes, LMP must be rapidly resolved, although the underlying mechanisms are poorly understood. Here, using an unbiased proteomic approach, we show that LMP stimulates a phosphoinositide-initiated membrane tethering and lipid transport (PITT) pathway for rapid lysosomal repair. Upon LMP, phosphatidylinositol-4 kinase type 2α (PI4K2A) accumulates rapidly on damaged lysosomes, generating high levels of the lipid messenger phosphatidylinositol-4-phosphate. Lysosomal phosphatidylinositol-4-phosphate in turn recruits multiple oxysterol-binding protein (OSBP)-related protein (ORP) family members, including ORP9, ORP10, ORP11 and OSBP, to orchestrate extensive new membrane contact sites between damaged lysosomes and the endoplasmic reticulum. The ORPs subsequently catalyse robust endoplasmic reticulum-to-lysosome transfer of phosphatidylserine and cholesterol to support rapid lysosomal repair. Finally, the lipid transfer protein ATG2 is also recruited to damaged lysosomes where its activity is potently stimulated by phosphatidylserine. Independent of macroautophagy, ATG2 mediates rapid membrane repair through direct lysosomal lipid transfer. Together, our findings identify that the PITT pathway maintains lysosomal membrane integrity, with important implications for numerous age-related diseases characterized by impaired lysosomal function.
Topics: Autophagy-Related Proteins; Biological Transport; Cholesterol; Endoplasmic Reticulum; Intracellular Space; Lysosomes; Oxysterols; Phosphatidylinositol Phosphates; Phosphatidylinositols; Phosphatidylserines; Phosphotransferases (Alcohol Group Acceptor); Proteomics; Receptors, Steroid; Signal Transduction
PubMed: 36071159
DOI: 10.1038/s41586-022-05164-4 -
Cell Nov 2022Binding of arrestin to phosphorylated G protein-coupled receptors (GPCRs) is crucial for modulating signaling. Once internalized, some GPCRs remain complexed with...
Binding of arrestin to phosphorylated G protein-coupled receptors (GPCRs) is crucial for modulating signaling. Once internalized, some GPCRs remain complexed with β-arrestins, while others interact only transiently; this difference affects GPCR signaling and recycling. Cell-based and in vitro biophysical assays reveal the role of membrane phosphoinositides (PIPs) in β-arrestin recruitment and GPCR-β-arrestin complex dynamics. We find that GPCRs broadly stratify into two groups, one that requires PIP binding for β-arrestin recruitment and one that does not. Plasma membrane PIPs potentiate an active conformation of β-arrestin and stabilize GPCR-β-arrestin complexes by promoting a fully engaged state of the complex. As allosteric modulators of GPCR-β-arrestin complex dynamics, membrane PIPs allow for additional conformational diversity beyond that imposed by GPCR phosphorylation alone. For GPCRs that require membrane PIP binding for β-arrestin recruitment, this provides a mechanism for β-arrestin release upon translocation of the GPCR to endosomes, allowing for its rapid recycling.
Topics: beta-Arrestins; Phosphatidylinositols; Arrestins; beta-Arrestin 1; Receptors, G-Protein-Coupled
PubMed: 36368322
DOI: 10.1016/j.cell.2022.10.018 -
Cell Research Aug 2023Migrasomes are recently discovered organelles, which are formed on the ends or branch points of retraction fibers at the trailing edge of migrating cells. Previously, we...
Migrasomes are recently discovered organelles, which are formed on the ends or branch points of retraction fibers at the trailing edge of migrating cells. Previously, we showed that recruitment of integrins to the site of migrasome formation is essential for migrasome biogenesis. In this study, we found that prior to migrasome formation, PIP5K1A, a PI4P kinase which converts PI4P into PI(4,5)P, is recruited to migrasome formation sites. The recruitment of PIP5K1A results in generation of PI(4,5)P at the migrasome formation site. Once accumulated, PI(4,5)P recruits Rab35 to the migrasome formation site by interacting with the C-terminal polybasic cluster of Rab35. We further demonstrated that active Rab35 promotes migrasome formation by recruiting and concentrating integrin α5 at migrasome formation sites, which is likely mediated by the interaction between integrin α5 and Rab35. Our study identifies the upstream signaling events orchestrating migrasome biogenesis.
Topics: Phosphatidylinositols; Integrin alpha5; Organelles; Signal Transduction; rab GTP-Binding Proteins; Phosphatidylinositol 4,5-Diphosphate
PubMed: 37142675
DOI: 10.1038/s41422-023-00811-5 -
Science (New York, N.Y.) Dec 2021Cytokinetic membrane abscission is a spatially and temporally regulated process that requires ESCRT (endosomal sorting complexes required for transport)–dependent...
Cytokinetic membrane abscission is a spatially and temporally regulated process that requires ESCRT (endosomal sorting complexes required for transport)–dependent control of membrane remodeling at the midbody, a subcellular organelle that defines the cleavage site. Alteration of ESCRT function can lead to cataract, but the underlying mechanism and its relation to cytokinesis are unclear. We found a lens-specific cytokinetic process that required PI3K-C2α (phosphatidylinositol-4-phosphate 3-kinase catalytic subunit type 2α), its lipid product PI(3,4)P (phosphatidylinositol 3,4-bisphosphate), and the PI(3,4)P–binding ESCRT-II subunit VPS36 (vacuolar protein-sorting-associated protein 36). Loss of each of these components led to impaired cytokinesis, triggering premature senescence in the lens of fish, mice, and humans. Thus, an evolutionarily conserved pathway underlies the cell type–specific control of cytokinesis that helps to prevent early onset cataract by protecting from senescence.
Topics: Aging, Premature; Animals; Biological Evolution; Calcium-Binding Proteins; Cataract; Cell Cycle Proteins; Cell Line; Cellular Senescence; Cytokinesis; Endosomal Sorting Complexes Required for Transport; Humans; Lens, Crystalline; Mice; Mutation; Phosphatidylinositol 3-Kinases; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositols; Tubulin; Zebrafish; Zebrafish Proteins
PubMed: 34882480
DOI: 10.1126/science.abk0410 -
Nature Communications Oct 2023Exosomes are secreted to the extracellular milieu when multivesicular endosomes (MVEs) dock and fuse with the plasma membrane. However, MVEs are also known to fuse with...
Exosomes are secreted to the extracellular milieu when multivesicular endosomes (MVEs) dock and fuse with the plasma membrane. However, MVEs are also known to fuse with lysosomes for degradation. How MVEs are directed to the plasma membrane for exosome secretion rather than to lysosomes is unclear. Here we report that a conversion of phosphatidylinositol-3-phosphate (PI(3)P) to phosphatidylinositol-4-phosphate (PI(4)P) catalyzed sequentially by Myotubularin 1 (MTM1) and phosphatidylinositol 4-kinase type IIα (PI4KIIα) on the surface of MVEs mediates the recruitment of the exocyst complex. The exocyst then targets the MVEs to the plasma membrane for exosome secretion. We further demonstrate that disrupting PI(4)P generation or exocyst function blocked exosomal secretion of Programmed death-ligand 1 (PD-L1), a key immune checkpoint protein in tumor cells, and led to its accumulation in lysosomes. Together, our study suggests that the PI(3)P to PI(4)P conversion on MVEs and the recruitment of the exocyst direct the exocytic trafficking of MVEs for exosome secretion.
Topics: Exosomes; Endosomes; Phosphatidylinositols; Multivesicular Bodies
PubMed: 37898620
DOI: 10.1038/s41467-023-42661-0 -
Scientific Reports Apr 2022Phosphoinositide-3-Kinase Regulatory Subunit 1 (PIK3R1) is believed to function as a tumor suppressor, while Phosphoinositide-3-Kinase Regulatory Subunit 2 (PIK3R2) as a...
Phosphoinositide-3-Kinase Regulatory Subunit 1 (PIK3R1) is believed to function as a tumor suppressor, while Phosphoinositide-3-Kinase Regulatory Subunit 2 (PIK3R2) as a tumor driver. However, there is no systematic pan-cancer analysis of them. The pan-cancer study comprehensively investigated the gene expression, genetic alteration, DNA methylation, and prognostic significance of PIK3R1 and PIK3R2 in 33 different tumors based on the TIMER, GEPIA, UALCAN, HPA, cBioPortal, and Kaplan-Meier Plotter database. The results indicated that PIK3R1 is lowly expressed in most tumors while PIK3R2 is highly expressed in most tumors, and abnormal gene expression may be related to promoter methylation. Moreover, not only mutations, downregulation of PIK3R1 and upregulation of PIK3R2 were found to be detrimental to the survival of most cancer patients as well. Furthermore, the expression of both PIK3R1 and PIK3R2 was associated with the level of immune infiltration in multiple tumors, such as breast invasive carcinoma. Our study conducted a comparatively comprehensive analysis of the role of PIK3R1 and PIK3R2 in a variety of cancers, contributing to further study of their potential mechanisms in cancer occurrence and progression. Our findings suggested that PIK3R1 and PIK3R2 could serve as prognostic markers for several cancers.
Topics: Class Ia Phosphatidylinositol 3-Kinase; Down-Regulation; Genes, Regulator; Humans; Neoplasms; Phosphatidylinositol 3-Kinases; Phosphatidylinositols; Prognosis
PubMed: 35395865
DOI: 10.1038/s41598-022-09889-0 -
Cell Proliferation Sep 2022Traumatic spinal cord injury (TSCI) causes neurological dysfunction below the injured segment of the spinal cord, which significantly impacts the quality of life in... (Review)
Review
OBJECTS
Traumatic spinal cord injury (TSCI) causes neurological dysfunction below the injured segment of the spinal cord, which significantly impacts the quality of life in affected patients. The phosphoinositide 3kinase/serine-threonine kinase (PI3K/AKT) signaling pathway offers a potential therapeutic target for the inhibition of secondary TSCI. This review summarizes updates concerning the role of the PI3K/AKT pathway in TSCI.
MATERIALS AND METHODS
By searching articles related to the TSCI field and the PI3K/AKT signaling pathway, we summarized the mechanisms of secondary TSCI and the PI3K/AKT signaling pathway; we also discuss current and potential future treatment methods for TSCI based on the PI3K/AKT signaling pathway.
RESULTS
Early apoptosis and autophagy after TSCI protect the body against injury; a prolonged inflammatory response leads to the accumulation of pro-inflammatory factors and excessive apoptosis, as well as excessive autophagy in the surrounding normal nerve cells, thus aggravating TSCI in the subacute stage of secondary injury. Initial glial scar formation in the subacute phase is a protective mechanism for TSCI, which limits the spread of damage and inflammation. However, mature scar tissue in the chronic phase hinders axon regeneration and prevents the recovery of nerve function. Activation of PI3K/AKT signaling pathway can inhibit the inflammatory response and apoptosis in the subacute phase after secondary TSCI; inhibiting this pathway in the chronic phase can reduce the formation of glial scar.
CONCLUSION
The PI3K/AKT signaling pathway has an important role in the recovery of spinal cord function after secondary injury. Inducing the activation of PI3K/AKT signaling pathway in the subacute phase of secondary injury and inhibiting this pathway in the chronic phase may be one of the potential strategies for the treatment of TSCI.
Topics: Apoptosis; Axons; Gliosis; Humans; Inflammation; Nerve Regeneration; Phosphatidylinositol 3-Kinases; Phosphatidylinositols; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-akt; Quality of Life; Signal Transduction; Spinal Cord Injuries
PubMed: 35754255
DOI: 10.1111/cpr.13275 -
Cells Apr 2020Phosphatidylinositol and its phosphorylated derivatives, the phosphoinositides, play many important roles in all eukaryotic cells. These include modulation of physical... (Review)
Review
Phosphatidylinositol and its phosphorylated derivatives, the phosphoinositides, play many important roles in all eukaryotic cells. These include modulation of physical properties of membranes, activation or inhibition of membrane-associated proteins, recruitment of peripheral membrane proteins that act as effectors, and control of membrane trafficking. They also serve as precursors for important second messengers, inositol (1,4,5) trisphosphate and diacylglycerol. Animal models and human diseases involving defects in phosphoinositide regulatory pathways have revealed their importance for function in the mammalian retina and retinal pigmented epithelium. New technologies for localizing, measuring and genetically manipulating them are revealing new information about their importance for the function and health of the vertebrate retina.
Topics: Humans; Phosphatidylinositols; Phosphorylation; Protein Transport; Retina; Retinal Diseases; Signal Transduction
PubMed: 32252387
DOI: 10.3390/cells9040866