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Current Opinion in Cell Biology Apr 2020Phosphoinositides (PPIns) are lipid signaling molecules that act as master regulators of cellular signaling. Recent studies have revealed novel roles of PPIns in myriad... (Review)
Review
Phosphoinositides (PPIns) are lipid signaling molecules that act as master regulators of cellular signaling. Recent studies have revealed novel roles of PPIns in myriad cellular processes and multiple human diseases mediated by misregulation of PPIn signaling. This review will present a timely summary of recent discoveries in PPIn biology, specifically their role in regulating unexpected signaling pathways, modification of signaling outcomes downstream of integral membrane proteins, and novel roles in lipid transport. This has revealed new roles of PPIns in regulating membrane trafficking, immunity, cell polarity, and response to extracellular signals. A specific focus will be on novel opportunities to target PPIn metabolism for treatment of human diseases, including cancer, pathogen infection, developmental disorders, and immune disorders.
Topics: Biological Transport; Humans; Phosphatidylinositols; Signal Transduction
PubMed: 31972475
DOI: 10.1016/j.ceb.2019.12.007 -
Journal of Lipid Research Jan 2010The phosphoinositide (PI) cycle, discovered over 50 years ago by Mabel and Lowell Hokin, describes a series of biochemical reactions that occur on the inner leaflet of... (Review)
Review
The phosphoinositide (PI) cycle, discovered over 50 years ago by Mabel and Lowell Hokin, describes a series of biochemical reactions that occur on the inner leaflet of the plasma membrane of cells in response to receptor activation by extracellular stimuli. Studies from our laboratory have shown that the retina and rod outer segments (ROSs) have active PI metabolism. Biochemical studies revealed that the ROSs contain the enzymes necessary for phosphorylation of phosphoinositides. We showed that light stimulates various components of the PI cycle in the vertebrate ROS, including diacylglycerol kinase, PI synthetase, phosphatidylinositol phosphate kinase, phospholipase C, and phosphoinositide 3-kinase (PI3K). This article describes recent studies on the PI3K-generated PI lipid second messengers in the control and regulation of PI-binding proteins in the vertebrate retina.
Topics: Animals; Diabetic Retinopathy; Humans; Phosphatidylinositol 3-Kinases; Phosphatidylinositols; Phosphorylation; Protein Subunits; Protein Tyrosine Phosphatases; Retina; Retinal Cone Photoreceptor Cells; Signal Transduction
PubMed: 19638643
DOI: 10.1194/jlr.R000232 -
Journal of Cell Science Mar 2022Phosphatidylinositol(4,5)-bisphosphate (PtdInsP2) is an important modulator of many cellular processes, and its abundance in the plasma membrane is closely regulated. We...
Phosphatidylinositol(4,5)-bisphosphate (PtdInsP2) is an important modulator of many cellular processes, and its abundance in the plasma membrane is closely regulated. We examined the hypothesis that members of the Dishevelled scaffolding protein family can bind the lipid kinases phosphatidylinositol 4-kinase (PI4K) and phosphatidylinositol 4-phosphate 5-kinase (PIP5K), facilitating synthesis of PtdInsP2 directly from phosphatidylinositol. We used several assays for PtdInsP2 to examine the cooperative function of phosphoinositide kinases and the Dishevelled protein Dvl3 in the context of two receptor signaling cascades. Simultaneous overexpression of PI4KIIIα (also known as PI4KA) and PIP5KIγ (also known as PIP5K1C) had a synergistic effect on PtdInsP2 synthesis that was recapitulated by overexpression of Dvl3. Increasing the activity of Dvl3 by overexpression increased resting plasma membrane PtdInsP2. Knockdown of Dvl3 reduced resting plasma membrane PtdInsP2 and slowed PtdInsP2 resynthesis following receptor activation. We confirm that Dvl3 promotes coupling of PI4KIIIα and PIP5KIγ and show that this interaction is essential for efficient resynthesis of PtdInsP2 following receptor activation.
Topics: 1-Phosphatidylinositol 4-Kinase; Cell Membrane; Dishevelled Proteins; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositols; Phosphotransferases (Alcohol Group Acceptor)
PubMed: 34982154
DOI: 10.1242/jcs.259145 -
Proceedings of the National Academy of... Aug 2016The phosphatidylinositol phosphate kinase (PIPK) family of enzymes is primarily responsible for converting singly phosphorylated phosphatidylinositol derivatives to...
The phosphatidylinositol phosphate kinase (PIPK) family of enzymes is primarily responsible for converting singly phosphorylated phosphatidylinositol derivatives to phosphatidylinositol bisphosphates. As such, these kinases are central to many signaling and membrane trafficking processes in the eukaryotic cell. The three types of phosphatidylinositol phosphate kinases are homologous in sequence but differ in catalytic activities and biological functions. Type I and type II kinases generate phosphatidylinositol 4,5-bisphosphate from phosphatidylinositol 4-phosphate and phosphatidylinositol 5-phosphate, respectively, whereas the type III kinase produces phosphatidylinositol 3,5-bisphosphate from phosphatidylinositol 3-phosphate. Based on crystallographic analysis of the zebrafish type I kinase PIP5Kα, we identified a structural motif unique to the kinase family that serves to recognize the monophosphate on the substrate. Our data indicate that the complex pattern of substrate recognition and phosphorylation results from the interplay between the monophosphate binding site and the specificity loop: the specificity loop functions to recognize different orientations of the inositol ring, whereas residues flanking the phosphate binding Arg244 determine whether phosphatidylinositol 3-phosphate is exclusively bound and phosphorylated at the 5-position. This work provides a thorough picture of how PIPKs achieve their exquisite substrate specificity.
Topics: Animals; Binding Sites; Crystallography, X-Ray; Models, Molecular; Phosphatidylinositol Phosphates; Phosphatidylinositols; Phosphorylation; Phosphotransferases (Alcohol Group Acceptor); Protein Binding; Protein Domains; Substrate Specificity; Zebrafish Proteins
PubMed: 27439870
DOI: 10.1073/pnas.1522112113 -
Biochemical Society Symposium 2007PH (pleckstrin homology) domains represent the 11th most common domain in the human proteome. They are best known for their ability to bind phosphoinositides with high... (Review)
Review
PH (pleckstrin homology) domains represent the 11th most common domain in the human proteome. They are best known for their ability to bind phosphoinositides with high affinity and specificity, although it is now clear that less than 10% of all PH domains share this property. Cases in which PH domains bind specific phosphoinositides with high affinity are restricted to those phosphoinositides that have a pair of adjacent phosphates in their inositol headgroup. Those that do not [PtdIns3P, PtdIns5P and PtdIns(3,5)P2] are instead recognized by distinct classes of domains including FYVE domains, PX (phox homology) domains, PHD (plant homeodomain) fingers and the recently identified PROPPINs (b-propellers that bind polyphosphoinositides). Of the 90% of PH domains that do not bind strongly and specifically to phosphoinositides, few are well understood. One group of PH domains appears to bind both phosphoinositides (with little specificity) and Arf (ADP-ribosylation factor) family small G-proteins, and are targeted to the Golgi apparatus where both phosphoinositides and the relevant Arfs are both present. Here, the PH domains may function as coincidence detectors. A central challenge in understanding the majority of PH domains is to establish whether the very low affinity phosphoinositide binding reported in many cases has any functional relevance. For PH domains from dynamin and from Dbl family proteins, this weak binding does appear to be functionally important, although its precise mechanistic role is unclear. In many other cases, it is quite likely that alternative binding partners are more relevant, and that the observed PH domain homology represents conservation of structural fold rather than function.
Topics: Binding Sites; Humans; Models, Molecular; Phosphatidylinositols; Protein Binding; Protein Structure, Tertiary; Sensitivity and Specificity
PubMed: 17233582
DOI: 10.1042/BSS0740081 -
Journal of Lipid Research Feb 2019Phosphoinositide membrane signaling is critical for normal physiology, playing well-known roles in diverse human pathologies. The basic mechanisms governing... (Review)
Review
Phosphoinositide membrane signaling is critical for normal physiology, playing well-known roles in diverse human pathologies. The basic mechanisms governing phosphoinositide signaling within the nucleus, however, have remained deeply enigmatic owing to their presence outside the nuclear membranes. Over 40% of nuclear phosphoinositides can exist in this non-membrane state, held soluble in the nucleoplasm by nuclear proteins that remain largely unidentified. Recently, two nuclear proteins responsible for solubilizing phosphoinositides were identified, steroidogenic factor-1 (SF-1; NR5A1) and liver receptor homolog-1 (LRH-1; NR5A2), along with two enzymes that directly remodel these phosphoinositide/protein complexes, phosphatase and tensin homolog (PTEN; MMAC) and inositol polyphosphate multikinase (IPMK; ipk2). These new footholds now permit the assignment of physiological functions for nuclear phosphoinositides in human diseases, such as endometriosis, nonalcoholic fatty liver disease/steatohepatitis, glioblastoma, and hepatocellular carcinoma. The unique nature of nuclear phosphoinositide signaling affords extraordinary clinical opportunities for new biomarkers, diagnostics, and therapeutics. Thus, phosphoinositide biology within the nucleus may represent the next generation of low-hanging fruit for new drugs, not unlike what has occurred for membrane phosphatidylinositol 3-kinase drug development. This review connects recent basic science discoveries in nuclear phosphoinositide signaling to clinical pathologies, with the hope of inspiring development of new therapies.
Topics: Animals; Disease; Health; Humans; Phosphatidylinositols; Receptors, Cytoplasmic and Nuclear; Signal Transduction
PubMed: 30201631
DOI: 10.1194/jlr.R088518 -
Polyphosphoinositide-Binding Domains: Insights from Peripheral Membrane and Lipid-Transfer Proteins.Advances in Experimental Medicine and... 2019Within eukaryotic cells, biochemical reactions need to be organized on the surface of membrane compartments that use distinct lipid constituents to dynamically modulate... (Review)
Review
Within eukaryotic cells, biochemical reactions need to be organized on the surface of membrane compartments that use distinct lipid constituents to dynamically modulate the functions of integral proteins or influence the selective recruitment of peripheral membrane effectors. As a result of these complex interactions, a variety of human pathologies can be traced back to improper communication between proteins and membrane surfaces; either due to mutations that directly alter protein structure or as a result of changes in membrane lipid composition. Among the known structural lipids found in cellular membranes, phosphatidylinositol (PtdIns) is unique in that it also serves as the membrane-anchored precursor of low-abundance regulatory lipids, the polyphosphoinositides (PPIn), which have restricted distributions within specific subcellular compartments. The ability of PPIn lipids to function as signaling platforms relies on both non-specific electrostatic interactions and the selective stereospecific recognition of PPIn headgroups by specialized protein folds. In this chapter, we will attempt to summarize the structural diversity of modular PPIn-interacting domains that facilitate the reversible recruitment and conformational regulation of peripheral membrane proteins. Outside of protein folds capable of capturing PPIn headgroups at the membrane interface, recent studies detailing the selective binding and bilayer extraction of PPIn species by unique functional domains within specific families of lipid-transfer proteins will also be highlighted. Overall, this overview will help to outline the fundamental physiochemical mechanisms that facilitate localized interactions between PPIn lipids and the wide-variety of PPIn-binding proteins that are essential for the coordinate regulation of cellular metabolism and membrane dynamics.
Topics: Carrier Proteins; Cell Membrane; Humans; Phosphatidylinositol Phosphates; Phosphatidylinositols; Protein Binding; Protein Domains; Signal Transduction
PubMed: 30483964
DOI: 10.1007/5584_2018_288 -
Trends in Cell Biology Oct 2005Phosphoinositide lipids function as both signaling molecules and as compartment-specific localization signals for phosphoinositide-binding proteins. In recent years,... (Review)
Review
Phosphoinositide lipids function as both signaling molecules and as compartment-specific localization signals for phosphoinositide-binding proteins. In recent years, both phosphoinositides and phosphoinositide-binding proteins have been reported to display a restricted, rather than a uniform, distribution across intracellular membranes. Here, we examine recent data documenting the restricted distribution of both phosphoinositides and phosphoinositide-binding proteins and examine how phosphoinositide-binding proteins might engage multiple binding partners to achieve these restricted localizations, effectively acting as detectors of coincident localization signals.
Topics: Enzyme Activation; Lipid Metabolism; Lipids; Membrane Microdomains; Models, Molecular; Molecular Structure; Phosphatidylinositols; Second Messenger Systems
PubMed: 16139503
DOI: 10.1016/j.tcb.2005.08.005 -
Molecular Biology of the Cell Jan 2017Phosphoinositides (PIPs) are key regulators of membrane traffic and signaling. The interconversion of PIPs by lipid kinases and phosphatases regulates their...
Phosphoinositides (PIPs) are key regulators of membrane traffic and signaling. The interconversion of PIPs by lipid kinases and phosphatases regulates their functionality. Phosphatidylinositol (PI) and PIPs have a unique enrichment of 1-stearoyl-2-arachidonyl acyl species; however, the regulation and function of this specific acyl profile remains poorly understood. We examined the role of the PI acyltransferase LYCAT in control of PIPs and PIP-dependent membrane traffic. LYCAT silencing selectively perturbed the levels and localization of phosphatidylinositol-4,5-bisphosphate [PI(4,5)P] and phosphatidylinositol-3-phosphate and the membrane traffic dependent on these specific PIPs but was without effect on phosphatidylinositol-4-phosphate or biosynthetic membrane traffic. The acyl profile of PI(4,5)P was selectively altered in LYCAT-deficient cells, whereas LYCAT localized with phosphatidylinositol synthase. We propose that LYCAT remodels the acyl chains of PI, which is then channeled into PI(4,5)P Our observations suggest that the PIP acyl chain profile may exert broad control of cell physiology.
Topics: 1-Acylglycerol-3-Phosphate O-Acyltransferase; Acyltransferases; Cell Culture Techniques; Cell Line; Cell Membrane; Humans; Phosphatidylinositol Phosphates; Phosphatidylinositols; Phosphoric Monoester Hydrolases; Phosphotransferases; Protein Transport; Retinal Pigment Epithelium
PubMed: 28035047
DOI: 10.1091/mbc.E16-09-0668 -
Journal of Genetics Jul 2018Phosphoinositides are a class of membrane lipids that are found on several intracellular compartments and play diverse roles inside cells, such as vesicle formation,... (Review)
Review
Phosphoinositides are a class of membrane lipids that are found on several intracellular compartments and play diverse roles inside cells, such as vesicle formation, protein trafficking, endocytosis etc. Intracellular distribution and levels of phosphoinositides are regulated by enzymes that generate and breakdown these lipids as well as other proteins that associate with phosphoinositides. These events lead to differing levels of specific phosphoinositides on different intracellular compartments. At these intracellular locations, phosphoinositides and their associated proteins, such as Rab GTPases, dynamin and BAR domain-containing proteins, regulate a variety of membrane trafficking pathways. Neurodegenerative phenotypes in disorders such as Parkinson's disease (PD) can arise as a consequence of altered or hampered intracellular trafficking. Altered trafficking can cause proteins such as α-synuclein to aggregate intracellularly. Several trafficking pathways are regulated bymaster regulators such as LRRK2,which is known to regulate the activity of phosphoinositide effector proteins. Perturbing either the levels of phosphoinositides or their interactions with different proteins disrupts intracellular trafficking pathways, contributing to phenotypes often observed in disorders such as Alzheimer's or PDs. Thus, studying phosphoinositide regulation and its role in trafficking can give us a deeper understanding of the contribution of disrupted trafficking to neurodegenerative phenotypes.
Topics: Animals; Cell Membrane; Humans; Models, Biological; Neurodegenerative Diseases; Phenotype; Phosphatidylinositols; Protein Transport
PubMed: 30027907
DOI: No ID Found