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Phosphatidylinositol 3-kinases (PI3Ks) are critical regulators of many cellular processes including cell survival, proliferation, migration, cytoskeletal reorganization, and intracellular vesicular trafficking. They are a family of lipid kinases that phosphorylate membrane phosphoinositide lipids at the 3′ position of their inositol rings, and in m...
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... the clathrin lattice, PI3K-C2α metabolizes PI(4,5)P2 to PI(3,4)P2 in cooperation with the PI-5 0 -phosphatases ORCL and synaptojanin-1 [35,42]. Localized enrichments in PI(3,4)P2 enable the recruitment of endocytic accessory proteins such as sorting nexin-9, which interact with actin-branching activator Arp2/3 and dynamin, and ultimately generate constricting force at the neck of the CCPs [43][44][45][46] (Figure 3). Endocytosis is considered an important mechanism involved in down-regulation of receptor signaling events via the internalization of ligand-receptor complexes. ...
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... is considered an important mechanism involved in down-regulation of receptor signaling events via the internalization of ligand-receptor complexes. Notably however, evidence reported in the last two decades indicates that endocytosis can contribute to a form of intracellular signal transduction dubbed 'endosomal signaling' [47,48] (Figure 3). ...
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... multifunctional scaffold protein intersectin-1 has been identified as a binding partner of PI3K-C2β via interaction between its SH3 domain and the proline-rich region of PI3K-C2β [54]. A recent study demonstrated that the intersectin-1 also recruits the F-BAR domain-containing protein FCHSD2, which stimulates actin polymerization via activation of a WASP family protein, resulting in the formation of actin patches around the CCPs [55] (Figure 3). Cell migration is an actin remodeling-related cellular process that is also reportedly regulated by PI3K-C2β [29,40,56,57], suggesting that it may contribute to actin polymerization in the endocytic site via FCHSD2 recruitment. ...
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... with this, we have demonstrated that the class II PI3K isoforms C2α and C2β, but not class I or III isoforms, are required for clathrin-dependent fluid-phase endocytosis 'pinocytosis' in endothelial cells [58]. These observations indicate that PI3K-C2α and PI3K-C2β play different indispensable roles in clathrinmediated endocytosis (Figure 3). Interestingly, PI3K-C2β is also found to localize in late endosomes and lysosomes under starved conditions, where it suppresses the activity of mTORC1 [59]. ...
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... addition, it has been demonstrated that the PI(3,4)P2 produced by PI3K-C2γ regulates long-termed early endosomal Akt activation during insulin signaling [30]. Class II PI3K isoforms may therefore generate spatially distinct pools of PI(3)P or PI(3,4)P2, which are linked to endocytic events and endosomal signal transduction in a contextdependent manner (Figure 3), although several reports indicate that class II PI3Ks are involved in autophagy regulation [61][62][63]. ...
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... There are three class II isoforms, PI3KC2α, 2β, 2γ, which may constitutively bind to membranes and require additional activation signals. There is a single class III PI3K, vacuolar protein sorting 34 (VPS34), which is required for membrane trafficking between the plasma membrane and the early endosomes [11]. PKB is a serine/threonine kinase that functions downstream of PI3K as well as the principal effector kinase for the PI3K/AKT pathway. ...
Diabetes as a fastest growing diseases worldwide is characterized by elevated blood glucose levels. There’s an enormous financial burden associated with this endocrine disorder, with unequal access to health care between developed and developing countries. PI3Ks (phosphoinositide 3-kinases) have been demonstrated to be crucial for glucose homeostasis, and malfunctioning of these molecules can contribute to an increase in glucose serum levels, the main pathophysiological feature of diabetes. Additionally, recent evidence suggests that miRNAs and lncRNAs are reciprocally interacting with this signaling pathway. It is therefore evident that abnormal regulation of miRNAs/lncRNAs in the lncRNAs/miRNAs/PI3K/AKT axis is related to clinicopathological characteristics and plays a crucial role in the regulation of biological processes. It has therefore been attempted in this review to describe the interaction between PI3K/AKT signaling pathway and various miRNAs/lncRNAs and their importance in DM biology. We also presented the clinical applications of PI3K/AKT-related ncRNAs/herbal medicine in patients with DM.
... Differently to other protein kinases, lipid kinases catalyse the ATP-dependent transferase reaction on lipid membranes, thereby localizing signalling reactions on membrane surfaces (Feng and Yu, 2021;Yoshioka, 2021;Burke et al., 2022). Therefore, alteration of lipid kinases activity is rarely associated with either inhibition or mistargeting of specific trafficking routes (Ronan et al., 2014). ...
... Nonetheless, Pitcoin3, an ATP-competitive PI3KC2α inhibitor, was recently developed to block clathrin-mediated endocytosis. By reducing plasma membrane and endosomal phosphoinositide's content (i.e., PtdIns(3,4)P2 and PtdIns(3)P) Pitcoin3 mimicks the effects of enzyme's genetic loss (Posor et al., 2013;Campa et al., 2018;Yoshioka, 2021;Lo et al., 2022). ...
Over the past years a growing number of studies highlighted the pivotal role of intracellular trafficking in cell physiology. Among the distinct transport itineraries connecting the endocytic system, both internalization (endocytosis) and recycling (endocytic recycling) pathways were found fundamental to ensure cellular sensing, cell-to-cell communication, cellular division, and collective cell migration in tissue specific-contexts. Consistently, the dysregulation of endocytic trafficking pathways is correlated with several human diseases including both cancers and neurodegeneration. Aimed at suppress specific intracellular trafficking routes involved in disease onset and progression, huge efforts have been made to identify small molecule inhibitors with suitable pharmacological properties for in vivo administration. Here, we review most used drugs and recently discovered small molecules able to block endocytosis and endocytic recycling pathways. We characterize such pharmacological inhibitors by emphasizing their target specificity, molecular affinity, biological activity and efficacy in both in vitro and in vivo experimental models.
... Indeed, confocal imaging showed PI(3)P tightly concentrated at prey cells that were clearly still attached to the substrate ( Fig 4G). These data contrast to macrophages that localize PI(3)P only following phagocytic cup closure and during phagosome maturation [35,[42][43][44][45], suggesting a novel role for PI(3)P generation in engulfment by senescent cells. ...
Cancer cells survive chemotherapy and cause lethal relapse by entering a senescent state that facilitates expression of many phagocytosis/macrophage-related genes that engender a novel cannibalism phenotype. We used biosensors and live-cell imaging to reveal the basic steps and mechanisms of engulfment by senescent human and mouse tumor cells. We show filamentous actin in predator cells was localized to the prey cell throughout the process of engulfment. Biosensors to various phosphoinositide (PI) species revealed increased concentration and distinct localization of predator PI(4) P and PI(4,5)P2 at the prey cell during early stages of engulfment, followed by a transient burst of PI(3) P before and following internalization. PIK3C2B, the kinase responsible for generating PI(3)P, was required for complete engulfment. Inhibition or knockdown of Clathrin, known to associate with PIK3C2B and PI(4,5)P2, severely impaired engulfment. In sum, our data reveal the most fundamental cellular processes of senescent cell engulfment, including the precise localizations and dynamics of actin and PI species throughout the entire process.
... Composition and Classification of Phosphatidylinositol-3-Kinase Serine/threonine and lipid kinases, including phosphomembrane-bound phosphatidylinositol-3 (PIP3) kinases, constitute the phosphatidylinositol-3-kinase (PI3K) family (Stefani et al., 2021;Yoshioka, 2021). These enzymes, along with the downstream Akt and rapamycin targets (mTOR), play considerable important roles in numerous key cellular processes such as growth, differentiation, metabolism, survival, and proliferation and so on (Miricescu et al., 2020;. ...
... These enzymes, along with the downstream Akt and rapamycin targets (mTOR), play considerable important roles in numerous key cellular processes such as growth, differentiation, metabolism, survival, and proliferation and so on (Miricescu et al., 2020;. PI3K enzymes can be classified into class I, class II, and class III enzymes (Yoshioka, 2021). Class I PI3K is one of the most widest considered as aberrant class of enzyme which is associated with cancer (Fruman et al., 2017;Koundouros et al., 2020). ...
As is known to all, glioma, a global difficult problem, has a high malignant degree, high recurrence rate and poor prognosis. We analyzed and summarized signal pathway of the Hippo/YAP, PI3K/AKT/mTOR, miRNA, WNT/β-catenin, Notch, Hedgehog, TGF-β, TCS/mTORC1 signal pathway, JAK/STAT signal pathway, MAPK signaling pathway, the relationship between BBB and signal pathways and the mechanism of key enzymes in glioma. It is concluded that Yap1 inhibitor may become an effective target for the treatment of glioma in the near future through efforts of generation after generation. Inhibiting PI3K/Akt/mTOR, Shh, Wnt/β-Catenin, and HIF-1α can reduce the migration ability and drug resistance of tumor cells to improve the prognosis of glioma. The analysis shows that Notch1 and Sox2 have a positive feedback regulation mechanism, and Notch4 predicts the malignant degree of glioma. In this way, notch cannot only be treated for glioma stem cells in clinic, but also be used as an evaluation index to evaluate the prognosis, and provide an exploratory attempt for the direction of glioma treatment. MiRNA plays an important role in diagnosis, and in the treatment of glioma, VPS25, KCNQ1OT1, KB-1460A1.5, and CKAP4 are promising prognostic indicators and a potential therapeutic targets for glioma, meanwhile, Rheb is also a potent activator of Signaling cross-talk etc. It is believed that these studies will help us to have a deeper understanding of glioma, so that we will find new and better treatment schemes to gradually conquer the problem of glioma.
... The Class 1 (A and B) PI3Ks are recruited to the cell membrane in response to the extracellular signals transmitted by the growth Cells 2022, 11, 1735 6 of 21 factor receptors, which then phosphorylate the phospholipid, phosphatidylinositol-4,5bisphosphate (PtdIns (4,5) P2), at the C-terminal end to produce phosphatidylinositol-3,4,5-trisphosphate (PtdIns (3,4,5) P3) [109]. Moreover, there are three isoforms in Class 2, including PI3K2α/2β/2γ, which has a C-terminal extension formed by the C2 and PX domains, which is responsible for its association with PtdIns (4,5) P2-containing plasma membranes [110]. There is just a single isoform in Class 3, hVps34 [111]. ...
Alzheimer’s disease (AD) is a common age-related neurodegenerative disease that leads to memory loss and cognitive function damage due to intracerebral neurofibrillary tangles (NFTs) and amyloid-β (Aβ) protein deposition. The phosphoinositide-dependent protein kinase (PDK1)/protein kinase B (Akt) signaling pathway plays a significant role in neuronal differentiation, synaptic plasticity, neuronal survival, and neurotransmission via the axon–dendrite axis. The phosphorylation of PDK1 and Akt rises in the brain, resulting in phosphorylation of the TNF-α-converting enzyme (TACE) at its cytoplasmic tail (the C-terminal end), changing its internalization as well as its trafficking. The current review aimed to explain the mechanisms of the PDK1/Akt/TACE signaling axis that exerts its modulatory effect on AD physiopathology. We provide an overview of the neuropathological features, genetics, Aβ aggregation, Tau protein hyperphosphorylation, neuroinflammation, and aging in the AD brain. Additionally, we summarized the phosphoinositide 3-kinase (PI3K)/PDK1/Akt pathway-related features and its molecular mechanism that is dependent on TACE in the pathogenesis of AD. This study reviewed the relationship between the PDK1/Akt signaling pathway and AD, and discussed the role of PDK1/Akt in resisting neuronal toxicity by suppressing TACE expression in the cell membrane. This work also provides a perspective for developing new therapeutics targeting PDK1/Akt and TACE for the treatment of AD.
... PI3Ks are divided into three classes according to their structure, localisation and functional role. Class II PI3Ks are the least studied members of the PI3K family and include three isoforms with broad tissue expression, PI3K-C2α, PI3K-C2β and PI3K-C2γ [36]. Unlike class I and III PI3Ks, class II PI3Ks produce PI(3)P and PI(3,4)P2, but not PI(3,4,5)P3, possibly indicating modulation of different downstream signalling pathways [1,8]. ...
Phosphatidylinositol 3-kinases (PI3Ks) are a family of lipid kinases that regulate crucial cellular processes, including cell survival, proliferation and intracellular vesicular trafficking. PI3Ksphosphorylate the 3-hydroxyl position of phosphatidylinositol (PI), PI(4)P and PI(4,5)P. Three PI3Ks classes have been described, according to their structure, substrate preference, and function, of which class II PI3Ks are least investigated. Class II PI3K comprises the PI3K-C2α, PI3K-C2β, and PI3K-C2γ isoforms with different cellular localisations involved in vesicular trafficking. PI3K-C2β, in particular, regulates endocytosis and endosomal signalling and, therefore, could interfere with the life-cycle of viruses that depend on the endosomal pathway for trafficking and morphogenesis, such as the Hepatitis B virus (HBV). HBV is an important human pathogen causing severe liver disease and hepatocellular carcinoma development, which results in the death of more than 500.000 chronically-infected patients every year. In this study, we modulated PI3K-C2β expression in hepatoma cells by using the CRISPR/Cas9 genome editing technology and investigated the consequences on HBV production. Our results showed significant inhibition of HBV particles release from cells depleted of PI3K-C2β, adding to the repertoire of host cell factors regulating HBV production, a novel target for the potential development of antiviral inhibitors. © 2022, Romanian Society for Pharmaceutical Sciences. All rights reserved.
... Activation of Met by HGF is more important in AU565, while the SK-BR-3 pathway depends more on PIK3CA signaling [62,63]. Rlip depletion has been shown to inhibit PIK3CA in other cancers [55,86,87], and both Rlip and PIK3CA are known to regulate CDE [55,[88][89][90]. Indeed, signaling initiated by growth factors including the EGF family (including Her3) and HGF is known to be broadly regulated by endocytosis of the receptor/ligand complex by CDE [91,92], and thus also by Rlip. ...
Her2-amplified breast cancers resistant to available Her2-targeted therapeutics continue to be a challenge in breast cancer therapy. Dox is the mainstay of chemotherapy of all types of breast cancer, but its usefulness is limited by cumulative cardiotoxicity. Because oxidative stress caused by dox generates the pro-apoptotic Ω-6 PUFA metabolite 4-hydroxynonenal (4-HNE), we surmised that Ω-6 PUFAs would increase the effectiveness of dox chemotherapy. Since the mercapturic acid pathway enzyme RALBP1 (also known as RLIP76 or Rlip) that limits cellular accumulation of 4-HNE also mediates dox resistance, the combination of Ω-6 PUFAs and Rlip depletion could synergistically improve the efficacy of dox. Thus, we studied the effects of the Ω-6 PUFA arachidonic acid (AA) and Rlip knockdown on the antineoplastic activity of dox towards Her2-amplified breast cancer cell lines SK-BR-3, which is sensitive to Her2 inhibitors, and AU565, which is resistant. AA increased lipid peroxidation, 4-HNE generation, apoptosis, cellular dox concentration and dox cytotoxicity in both cell lines while sparing cultured immortalized cardiomyocyte cells. The known functions of Rlip including clathrin-dependent endocytosis and dox efflux were inhibited by AA. Our results support a model in which 4-HNE generated by AA overwhelms the capacity of Rlip to defend against apoptosis caused by dox or 4-HNE. We propose that Ω-6 PUFA supplementation could improve the efficacy of dox or Rlip inhibitors for treating Her2-amplified breast cancer.
Ischemia-reperfusion is a cascade of complex and interrelated pathological processes underlying many human diseases, including such socially significant as stroke, myocardial infarction, acute renal failure, etc. The present review considers modern ideas about the main biochemical and signal-regulatory processes occurring in the cell under conditions of ischemia-reperfusion. Both generally accepted and newly developed ways of ischemia-reperfusion lesion correction aimed at different chains of this pathological process are considered.
Ischemia–reperfusion is a cascade of complex and interrelated pathological processes underlying
many human diseases, including such socially significant diseases as stroke, myocardial infarction, acute
renal failure, etc. The present review considers modern ideas about the main biochemical and signal-regula-
tory processes in the cell under conditions of ischemia–reperfusion. Both generally accepted and newly
developed ways of ischemia–reperfusion lesion correction aimed at different chains of this pathological pro-
cess are considered.
