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In autophagy, cytoplasmic substrates are targeted for degradation in the lysosome via membrane structures called autophagosomes. The formation of the autophagosome is the primary regulatory point for autophagy activity, and PI3P p...
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In autophagy, cytoplasmic substrates are targeted for degradation in the lysosome via membrane structures called autophagosomes. The formation of the autophagosome is the primary regulatory point for autophagy activity, and PI3P plays a central role in this process. In this review, we will discuss the role of PI3P in autophagosome formation from three different perspectives: PI3-kinase, PI3-binding proteins, and PI3-phosphatase. Recent developments in this field suggest that the local PI3P concentration is dynamically regulated during autophagy, and that this molecule is critical to the proper control of autophagy.
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The Ciona intestinalis voltage sensitive phosphatase (Ci-VSP) was the first proven enzyme to be under direct control of the membrane potential. Ci-VSP belongs to a family of proteins known as Protein Tyrosine Phosphatases (PTP), w...
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The Ciona intestinalis voltage sensitive phosphatase (Ci-VSP) was the first proven enzyme to be under direct control of the membrane potential. Ci-VSP belongs to a family of proteins known as Protein Tyrosine Phosphatases (PTP), which are a group of enzymes that catalyze the removal of phosphate groups from phosphatidylinositides and phosphorylated tyrosine residues on proteins. What makes Ci-VSP and similar phosphatases unique is the presence of a Voltage Sensing Domain (VSD) in their N-terminus. The VSD of Ci-VSP shares high homology with those from voltage-gated channels and confers voltage sensitivity to these enzymes. The catalytic domain of Ci-VSP displays extraordinary structural and functional similarities to PTEN. This latter protein is encoded by the Phosphatase and Tensin homolog deleted from chromosome 10 gene, thus its name, and it is known as a tumor suppressor. The resemblance between these proteins has prompted the use of PTEN as a template for the study of Ci-VSP and produced a rapid advance in our understanding of the mechanism of activity of Ci-VSP. This review will be focused on discussing recent advances in the understanding of the activation mechanism for these molecules known as electrochemical coupling.
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Macroautophagy is a major intracellular degradation system. We previously reported that overexpression of phosphatase-deficient MTMR3, a member of the myotubularin phosphatidylinositol (PI) 3-phosphatase family, leads to induction...
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Macroautophagy is a major intracellular degradation system. We previously reported that overexpression of phosphatase-deficient MTMR3, a member of the myotubularin phosphatidylinositol (PI) 3-phosphatase family, leads to induction of autophagy. In this study, we found that MTMR3 interacted with mTORC1, an evolutionarily conserved serine/threonine kinase complex, which regulates cell growth and autophagy in response to environmental stimuli. Furthermore, overexpression of MTMR3 inhibited mTORC1 activity. The N-terminal half of MTMR3, including the PH-G and phosphatase domains, was necessary and sufficient for these effects. Phosphatase-deficient MTMR3 provided more robust suppression of mTORC1 activity than wild-type MTMR3. Furthermore, phosphatase-deficient full length MTMR3 and the phosphatase domain alone were localized to the Golgi. These results suggest a new regulatory mechanism of mTORC1 in association with PI3P.
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Initially identified as a key phosphoinositide that controls membrane trafficking at the Golgi complex, phosphatidyl-inositol-4-phosphate (PI4P) has emerged as a key molecule in the regulation of a diverse array of cellular functi...
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Initially identified as a key phosphoinositide that controls membrane trafficking at the Golgi complex, phosphatidyl-inositol-4-phosphate (PI4P) has emerged as a key molecule in the regulation of a diverse array of cellular functions. In this review we will discuss selected examples of the findings that in the last few years have significantly increased our awareness of the regulation and roles of PI4P in the Golgi complex and beyond. We will also highlight the role of PI4P in infection and cancer. We believe that, with the increasing number of regulators and effectors of PI4P identified, the time is ripe for a more integrated approach of study. A first step in this direction is the delineation of PI4P-centered molecular networks that we provide using data from low and high throughput studies in yeast and mammals.
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ABSTRACT During recent decades, PI(4)P (phosphoinositol-4-phosphate) has been described as a key regulator of a wide range of cellular functions such as organelle biogenesis, lipid metabolism and distribution, membrane trafficking...
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ABSTRACT During recent decades, PI(4)P (phosphoinositol-4-phosphate) has been described as a key regulator of a wide range of cellular functions such as organelle biogenesis, lipid metabolism and distribution, membrane trafficking, ion channels, pumps, and transporter activities. In this review we will focus on the multiple mechanisms that regulate PI(4)P homeostasis ranging from those responsible for the spatial distribution of the PI4 kinases and PI(4)P phosphatase to those controlling their enzymatic activity or the delivery/presentation of the substrate, i.e. PI or PI(4)P, to the PI4Ks or PI(4)P phosphatase, respectively. We will also highlight the open questions in the field mainly dealing with the existence and mode of action of PI(4)P sensors that monitor its amount and can act as a rheostat tuning PI(4)P levels in different compartments and adapting them to the different needs of the cell.
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Phosphoinositides (PIs) have critical roles in various cellular, physiological, developmental, pathological, and infectious processes. They are signaling phospholipids that can affect every aspect of membrane biology, including pr...
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Phosphoinositides (PIs) have critical roles in various cellular, physiological, developmental, pathological, and infectious processes. They are signaling phospholipids that can affect every aspect of membrane biology, including protein function (e.g., recruitment and activity), membrane physicochemical properties (e.g., curvature, surface charges, and packing), and the generation of secondary messengers. PIs act at precise locations within the cell in a dose-dependent manner, and their local concentration can vary drastically during signaling and trafficking. Thus, techniques able to manipulate PI amounts acutely and with subcellular accuracy are paramount to understanding the role of these lipids in vivo. Here, we review these methods and emphasize approaches recently developed to perturb PI levels in multicellular organisms.
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The recently discovered voltage-sensitive phosphatases (VSPs) hydrolyze phosphoinositides upon depolarization of the membrane potential, thus representing a novel principle for the transduction of electrical activity into biochemi...
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The recently discovered voltage-sensitive phosphatases (VSPs) hydrolyze phosphoinositides upon depolarization of the membrane potential, thus representing a novel principle for the transduction of electrical activity into biochemical signals. Here, we demonstrate the possibility to confer voltage sensitivity to cytosolic enzymes. By fusing the tumor suppressor PTEN to the voltage sensor of the prototypic VSP from Ciona intestinalis, Ci-VSP, we generated chimeric proteins that are voltage-sensitive and display PTEN-like enzymatic activity in a strictly depolarization-dependent manner in vivo. Functional coupling of the exogenous enzymatic activity to the voltage sensor is mediated by a phospholipid-binding motif at the interface between voltage sensor and catalytic domains. Our findings reveal that the main domains of VSPs and related phosphoinositide phosphatases are intrinsically modular and define structural requirements for coupling of enzymatic activity to a voltage sensor domain. A key feature of this prototype of novel engineered voltage-sensitive enzymes, termed Ci-VSPTEN, is the novel ability to switch enzymatic activity of PTEN rapidly and reversibly. We demonstrate that experimental control of Ci-VSPTEN can be obtained either by electrophysiological techniques or more general techniques, using potassium-induced depolarization of intact cells. Thus, Ci-VSPTEN provides a novel approach for studying the complex mechanism of activation, cellular control, and pharmacology of this important tumor suppressor. Moreover, by inducing temporally precise perturbation of phosphoinositide concentrations, Ci-VSPTEN will be useful for probing the role and specificity of these messengers in many cellular processes and to analyze the timing of phosphoinositide signaling.
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Phosphoinositides are a group of lipids that regulate intracellular signaling and subcellular biological events. The signaling by phosphatidylinositol-3,4,5-trisphosphate and Akt mediates the action of growth factors that are esse...
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Phosphoinositides are a group of lipids that regulate intracellular signaling and subcellular biological events. The signaling by phosphatidylinositol-3,4,5-trisphosphate and Akt mediates the action of growth factors that are essential for cell proliferation, gene transcription, cell migration, and polarity. The hyperactivation of this signaling has been identified in different cancer cells; and, it has been implicated in oncogenic transformation and cancer cell malignancy. Recent studies have argued the role of phosphoinositides in cancer cell dynamics, including actin cytoskeletal rearrangement at the plasma membrane and the organization of intracellular compartments. The focus of this review is to summarize the impact of the activities of phosphoinositide phosphatases on intracellular signaling related to cancer cell dynamics and to discuss how the abnormalities in the activities of the enzymes alter the levels of phosphoinositides in cancer cells.
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ABSTRACT Human brain development is a complex process where multiple cellular and developmental events are coordinated to generate normal structure and function. Alteration in any of these events can impact brain development, mani...
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ABSTRACT Human brain development is a complex process where multiple cellular and developmental events are coordinated to generate normal structure and function. Alteration in any of these events can impact brain development, manifesting clinically as neurodevelopmental disorders. Human genetic disorders of lipid metabolism often present with features of altered brain function. Lowe syndrome (LS) is an X-linked recessive disease with features of altered brain function. LS results from mutations in OCRL1 , which encodes a phosphoinositide 5-phosphatase enzyme. However, the cellular mechanisms by which loss of OCRL1 leads to brain defects remain unknown. Human brain development involves several cellular and developmental features not conserved in other species and understanding such mechanisms remains a challenge. Rodent models of LS have been generated but failed to recapitulate features of the human disease. Here we describe the generation of human stem cell lines from LS patients. Further, we present biochemical characterization of lipid metabolism in patient cell lines and demonstrate their use as a ‘ disease-in-a-dish ’ model for understanding the mechanism by which loss of OCRL1 leads to altered cellular and physiological brain development.
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Numerous studies have confirmed that microRNAs (miRNAs or miRs) have important roles in cancer biogenesis and development including multiple myeloma (MM). MicroRNA-25-3p (miR-25-3p) has been proven to promote cancer progression, w...
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Numerous studies have confirmed that microRNAs (miRNAs or miRs) have important roles in cancer biogenesis and development including multiple myeloma (MM). MicroRNA-25-3p (miR-25-3p) has been proven to promote cancer progression, whereas its functions in MM has not yet been reported, at least to the best of our knowledge. Therefore, the present study aimed to investigate the function of miR-25-3p in MM and to identify the potential underlying mechanistic pathway. Herein, it was found that miR-25-3p expression was significantly increased in MM tissues and cell lines. The upregulation of miR-25-3p was closely associated with anemia, renal function impairment international staging system (ISS) staging and Durie-Salmon (D-S) staging. A high level of miR-25-3p was predictive of a poor prognosis of patients with MM. In vitro, the knockdown of miR-25-3p suppressed the proliferation and promoted the apoptosis of RPMI-8226 and U266 cells, while the overexpression of miR-25-3p exerted opposite effects. In addition, phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a well-known tumor suppressor, was confirmed as a target of miR-25-3p in MM cells. Moreover, it was found that the PTEN expression levels were decreased, and inversely correlated with miR-25-3p expression levels in MM tissues. Further analyses revealed that the overexpression of PTEN exerted effects similar to those of miR-25-3p knockdown, whereas the knockdown of PTEN partially abolished the effects of miR-25-3p inhibitor on MM cells. Accompanied by PTEN induction, miR-25-3p promoted PI3K/AKT signaling pathway activation in MM cells. Collectively, these findings demonstrate critical roles for miR-25-3p in the pathogenesis of MM, and suggest that miR-25-3p may serve as a novel prognostic biomarker and therapeutic target of MM.
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