Phosphoinositide signalling in Drosophila

Balakrishnan, Sruthi; Basu, Urbashi; Raghu, Padinjat

doi:10.1016/j.bbalip.2014.10.010

Cited by 42 publications

(38 citation statements)

References 118 publications

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“…Cyst cell knockdown of the Drosophila skittles (sktl) gene, encoding the dPIP5K kinase that synthesizes PIP2 from PI4K (Balakrishnan et al, 2015;Gervais et al, 2008), reduced the severity of both the dlg knockdown and EGFR CA overexpression phenotypes (Fig. 4).…”

Section: Lowering Levels Of Egfr Signal Transduction Pathway Componenmentioning

confidence: 99%

The Dlg-module and clathrin-mediated endocytosis regulate EGFR signaling and cyst cell-germline coordination in theDrosophilatestis

Papagiannouli

Berry

Fuller

2018

Preprint

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SUMMARYTissue homeostasis and repair relies on proper communication of stem cells and their differentiating daughters with the local tissue microenvironment. In the Drosophila male germline adult stem cell lineage, germ cells proliferate and progressively differentiate enclosed in supportive somatic cyst cells, forming a small organoid, the functional unit of differentiation. Here we show that cell polarity and vesicle trafficking influence signal transduction in cyst cells, with profound effects on the germ cells they enclose. Our data suggest that both the cortical components Dlg, Scrib, Lgl and the clathrin-mediated endocytic (CME) machinery downregulate EGFR signaling. Knockdown of dlg, scrib, lgl or CME components in cyst cells resulted in germ cell death, similar to increased signal transduction via the EGFR, while lowering EGFR or downstream signaling components rescued the defects. This work provides new insights on how cell polarity and endocytosis cooperate to regulate signal transduction and sculpt developing tissues.

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Section: Lowering Levels Of Egfr Signal Transduction Pathway Componenmentioning

confidence: 99%

The Dlg-module and clathrin-mediated endocytosis regulate EGFR signaling and cyst cell-germline coordination in theDrosophilatestis

Papagiannouli

Berry

Fuller

2018

Preprint

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“…The enzymes that regulate phosphoinositide metabolism are conserved in the Drosophila genome (Balakrishnan et al, 2015). The fly genome has three genes that encode orthologs of PI4K enzymes.…”

Section: Introductionmentioning

confidence: 99%

Regulation of PI4P levels by PI4KIIIα during G-protein-coupled PLC signaling in Drosophila photoreceptors

Balakrishnan

Basu

Shinde

et al. 2018

Journal of Cell Science

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The activation of phospholipase C (PLC) is a conserved mechanism of receptor-activated cell signaling at the plasma membrane. PLC hydrolyzes the minor membrane lipid phosphatidylinositol 4,5-bisphosphate [PI(4,5)P], and continued signaling requires the resynthesis and availability of PI(4,5)P at the plasma membrane. PI(4,5)P is synthesized by the phosphorylation of phosphatidylinositol 4-phosphate (PI4P). Thus, a continuous supply of PI4P is essential to support ongoing PLC signaling. While the enzyme PI4KA has been identified as performing this function in cultured mammalian cells, its function in the context of an physiological model has not been established. In this study, we show that, in photoreceptors, PI4KIIIα activity is required to support signaling during G-protein-coupled PLC activation. Depletion of PI4KIIIα results in impaired electrical responses to light, and reduced plasma membrane levels of PI4P and PI(4,5)P Depletion of the conserved proteins Efr3 and TTC7 [also known as StmA and L(2)k14710, respectively, in flies], which assemble PI4KIIIα at the plasma membrane, also results in an impaired light response and reduced plasma membrane PI4P and PI(4,5)P levels. Thus, PI4KIIIα activity at the plasma membrane generates PI4P and supports PI(4,5)P levels during receptor activated PLC signaling.

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“…The exact reasons for these conflicting results is unclear and may 398 include the different cell types used in each study; a key reason is likely to be the overlapping function 399 of the three PIP4K isoforms present in mammalian genomes. In this study, we found that in Drosophila, 400 that contains only a single gene encoding PIP4K activity (dPIP4K) (Balakrishnan et al, 2015;Gupta et 401 al., 2013), the levels of plasma membrane PIP3 in cells lacking dPIP4K were elevated compared to 402 controls. We established this finding using both a fluorescent reporter for plasma membrane PIP3 in 403 single cell assays using multiple cell types and also using lipid mass spectrometry across larval tissues 404 and cultured, dPIP4K depleted Drosophila S2 cells.…”

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confidence: 80%

Phosphatidylinositol 5 phosphate 4-kinase regulates plasma-membrane PIP₃ turnover and insulin sensitivity in Drosophila

Sharma

Mathre

Ramya

et al. 2018

Preprint

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27Phosphatidylinositol-3,4,5-trisphosphate (PIP3) generation at the plasma membrane is a key event 28 during activation of receptor tyrosine kinases such as the insulin receptor and is critical for normal 29 growth and metabolism. The lipid kinases and phosphatases regulating PIP3 levels are described but 30 mechanisms that control their activity remains unclear. We report that in Drosophila, 31phosphatidylinositol 5 phosphate 4-kinase (PIP4K) regulates PIP3 levels during insulin receptor 32 activation. Depletion of PIP4K increases PIP3 levels and augments sensitivity to insulin through 33 enhanced Class I phosphoinositide 3-kinase (PI3K) activity. Plasma membrane localized PIP4K was 34 sufficient to control PIP3 levels. Animals lacking PIP4K show enhanced insulin dependent phenotypes 35 in vivo and show resistance to the metabolic consequences of a high-sugar diet. Thus, PIP4K is required 36 for normal metabolism and development. Our work defines PIP4Ks as regulators of receptor tyrosine 37 kinase signalling with implications for growth factor dependent processes including tumour growth, T-38 cell activation and metabolism.Lipid kinases that can phosphorylate selected positions on the inositol head group of 58 phosphatidylinositol (PI), generate second messengers that regulate multiple processes in eukaryotic 59 cells. The generation of phosphatidylinositol 3,4,5-trisphosphate (PIP3) through the action of Class I 60 PI3K following growth factor receptor (e.g Insulin receptor) stimulation, is a widespread signalling 61 reaction (Hawkins et al., 2006) that regulates normal growth and development (Engelman et al., 2006). 62The role of Class I PI3K activation in response to insulin receptor signalling is evolutionarily conserved 63 and has been widely studied in metazoan models such as the fly, worm and mammals (Barbieri et al., 64 2003). Robust control of the levels and the dynamics of PIP3 turnover is essential to maintain fidelity and 65 sensitivity of information transfer during insulin signalling. This is achieved through a number of 66 different molecular mechanisms. The Class I PI3K enzyme is a dimer of a catalytic subunit (p110) whose 67 activity is inhibited under unstimulated conditions by the regulatory subunit (p85/50/55/60). Upstream 68 receptor activation and subsequent binding to p-Tyr residues on the receptor and adaptor proteins 69 relieves this inhibition. In addition, lipid phosphatases are also important in controlling PIP3 levels at 70 the plasma membrane. PTEN, a 3-phosphatase, hydrolyzes PIP3 to produce PI(4,5)P2 (McConnachie et 71 al., 2003) while SHIP2 is a 5-phosphate that generates PI(3,4)P2 from PIP3 (Pesesse et al., 1998). It is well 72 documented that mutations in genes encoding any of these enzymes can be oncogenic or result in 73 metabolic syndromes. Loss of function in PTEN or gain of function in Class I PI3K genes results in 74 tumour development (Luo et al., 2003) while loss of SHIP2 results in altered insulin sensitivity in 75 mammals (Clément et al., 2001; Kaisaki et al., ...

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Phosphoinositide signalling in Drosophila

Cited by 42 publications

References 118 publications

The Dlg-module and clathrin-mediated endocytosis regulate EGFR signaling and cyst cell-germline coordination in theDrosophilatestis

The Dlg-module and clathrin-mediated endocytosis regulate EGFR signaling and cyst cell-germline coordination in theDrosophilatestis

Regulation of PI4P levels by PI4KIIIα during G-protein-coupled PLC signaling in Drosophila photoreceptors

Phosphatidylinositol 5 phosphate 4-kinase regulates plasma-membrane PIP₃ turnover and insulin sensitivity in Drosophila

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Phosphoinositide signalling in Drosophila

Cited by 42 publications

References 118 publications

The Dlg-module and clathrin-mediated endocytosis regulate EGFR signaling and cyst cell-germline coordination in theDrosophilatestis

The Dlg-module and clathrin-mediated endocytosis regulate EGFR signaling and cyst cell-germline coordination in theDrosophilatestis

Regulation of PI4P levels by PI4KIIIα during G-protein-coupled PLC signaling in Drosophila photoreceptors

Phosphatidylinositol 5 phosphate 4-kinase regulates plasma-membrane PIP3 turnover and insulin sensitivity in Drosophila

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Phosphatidylinositol 5 phosphate 4-kinase regulates plasma-membrane PIP₃ turnover and insulin sensitivity in Drosophila