Probing phosphoinositide functions in signaling and membrane trafficking

Division of Cell Signalling, School of Life Sciences, MSI/WTB Complex, University of Dundee, Dundee DD1 5EH, Scotland, UK.
Trends in Cell Biology (Impact Factor: 12.01). 06/2005; 15(5):259-68. DOI: 10.1016/j.tcb.2005.03.008
Source: PubMed


The inositol phospholipids (PIs) comprise a family of eight species with different combinations of phosphate groups arranged around the inositol ring. PIs are among the most versatile signaling molecules known, with key roles in receptor-mediated signal transduction, actin remodeling and membrane trafficking. Recent studies have identified effector proteins and specific lipid-binding domains through which PIs signal. These lipid-binding domains can be used as probes to further our understanding of the spatial and temporal control of individual PI species. New layers of complexity revealed by the use of such probes include the occurrence of PIs at intracellular locations, the identification of phosphatidylinositol signaling hotspots and the presence of non-membrane pools of PIs in cell nuclei.

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    • "They function during exocytosis of membrane vesicles at the plasma membrane[12], in the budding of vesicles from the Golgi[13], and the fusion of mitochondrial membranes[14]. PIP n control several cellular events, such as cell proliferation, actin organization, membrane trafficking, cell differentiation and cell migration[15], but they also regulate lipid distribution[16]. The fact that the levels of PIP n are critical for spermatocyte cytokinesis is shown by the fwd (PI4 Kb) and giotto (PI transporter) mutants, in which actin dynamics are disturbed during cyto- kinesis17181920. "

    Full-text · Article · Jan 2016 · Open Biology
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    • "The generation of phosphatidylinositol (3,4,5) triphosphate [PtdIns(3,4,5)P3] by type I phosphoinositide (PI) 3-kinases is affected by a number of growth factors and cytokines, many of which are influenced by HSPGs as accessory molecules. PtdIns(3,4,5)P3 affects a number of trafficking events, including endocytosis and autophagy (Downes et al. 2005). "
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    ABSTRACT: The identification and validation of gene-gene interactions is a major challenge in human studies. Here, we explore an approach for studying epistasis in humans using a Drosophila melanogaster model of neonatal diabetes mellitus. Expression of the mutant preproinsulin (hINS(C96Y)) in the eye imaginal disc mimics the human disease: it activates conserved stress response pathways and leads to cell death (reduction in eye area). Dominant-acting variants in wild-derived inbred lines from the Drosophila Genetics Reference Panel produce a continuous, highly heritable distribution of eye degeneration phenotypes in a hINS(C96Y) background. A genome-wide association study (GWAS) in 154 sequenced lines identified a sharp peak on chromosome 3L, which mapped to a 400bp linkage block within an intron of the gene sulfateless (sfl). RNAi knock-down of sfl enhanced the eye degeneration phenotype in a mutant-hINS-dependent manner. RNAi against two additional genes in the heparan sulfate (HS) biosynthetic pathway (ttv and botv), in which sfl acts, also modified the eye phenotype in a hINS(C96Y)-dependent manner, strongly suggesting a novel link between HS-modified proteins and cellular responses to misfolded proteins. Finally, we evaluated allele-specific expression difference between the two major sfl-intronic haplotypes in heterozygtes. The results showed significant heterogeneity in marker-associated gene expression, thereby leaving the causal mutation(s) and its mechanism unidentified. In conclusion, the ability to create a model of human genetic disease, map a QTL by GWAS to a specific gene, validate its contribution to disease with available genetic resources, and the potential to experimentally link the variant to a molecular mechanism, demonstrate the many advantages Drosophila holds in determining the genetic underpinnings of human disease.
    Full-text · Article · Feb 2014 · Genetics
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    • "In addition to this, myo-inositol also contributes to plant protection against salinity by restoring the turgor pressure and protecting cellular structures from reactive oxygen species stress (Loewus and Murthy 2000; Majumder and Biswas 2006). Therefore, any changes in the levels of myo-inositol due to perturbation of MIPS may lead to alteration of the compounds synthesized later in the pathway, which can further disturb the signaling mechanism that regulates plants responses to different environmental stresses (Stevenson et al. 2000; Downes et al. 2005). Another important aspect of phytate reduction is associated with an increase in the amount of iron in seeds. "
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    ABSTRACT: Background Phytic acid (InsP6) is considered as the major source of phosphorus and inositol phosphates in cereal grains. Reduction of phytic acid level in cereal grains is desirable in view of its antinutrient properties to maximize mineral bioavailability and minimize the load of phosphorus waste management. We report here RNAi mediated seed-specific silencing of myo-inositol-3-phosphate synthase (MIPS) gene catalyzing the first step of phytic acid biosynthesis in rice. Moreover, we also studied the possible implications of MIPS silencing on myo-inositol and related metabolism, since, first step of phytic acid biosynthesis is also the rate limiting step of myo-inositol synthesis, catalyzed by MIPS. Results The resulting transgenic rice plants (T3) showed a 4.59 fold down regulation in MIPS gene expression, which corresponds to a significant decrease in phytate levels and a simultaneous increment in the amount of inorganic phosphate in the seeds. A diminution in the myo-inositol content of transgenic plants was also observed due to disruption of the first step of phytic acid biosynthetic pathway, which further reduced the level of ascorbate and altered abscisic acid (ABA) sensitivity of the transgenic plants. In addition, our results shows that in the transgenic plants, the lower phytate levels has led to an increment of divalent cations, of which a 1.6 fold increase in the iron concentration in milled rice seeds was noteworthy. This increase could be attributed to reduced chelation of divalent metal (iron) cations, which may correlate to higher iron bioavailability in the endosperm of rice grains. Conclusion The present study evidently suggests that seed-specific silencing of MIPS in transgenic rice plants can yield substantial reduction in levels of phytic acid along with an increase in inorganic phosphate content. However, it was also demonstrated that the low phytate seeds had an undesirable diminution in levels of myo-inositol and ascorbate, which probably led to sensitiveness of seeds to abscisic acid during germination. Therefore, it is suggested that though MIPS is the prime target for generation of low phytate transgenic plants, down-regulation of MIPS can have detrimental effect on myo-inositol synthesis and related pathways which are involved in key plant metabolism.
    Full-text · Article · Nov 2013 · Rice
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