scholarly journals A Mathematical Model of the Phosphoinositide Pathway

2017 ◽  
Author(s):  
Daniel V Olivença ◽  
Inna Uliyakina ◽  
Luis L Fonseca ◽  
Margarida D Amaral ◽  
Eberhard Voit ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Protein Kinase ◽  
Sodium Channel ◽  
Mammalian Cells ◽  
Sh2 Domain ◽  
Mass Action ◽  
Inositol Polyphosphate ◽  
Membrane Contact Sites ◽  
Lipid Phosphatase ◽  
Phosphoinositide Pathway

ABSTRACTPhosphoinositides are signaling lipids that constitute a complex network regulating many cellular processes. We propose a computational model that accounts for all known species of phosphoinositides in the plasma membrane of mammalian cells. The model replicates the steady-state of the phosphoinositide pathway and most known dynamic phenomena. Furthermore, sensitivity analysis demonstrates model robustness to moderate alterations in any of the parameters. Model analysis suggest that the greatest contributor to PI(4,5)P2production is a flux representing the direct transformation of PI into PI(4,5)P2and is also responsible for the maintenance of this pool when PI(4)P is decreased. PI(5)P is also shown to be a significant source for PI(4,5)P2production. The model was validated with data from siRNA screens that knocked down the expression of several enzymes in the pathway. The screen monitored the activity of the epithelium sodium channel, ENaC, which is activated by PI(4,5)P2. Moderating ENaC activity can have a therapeutic effect in Cystic Fibrosis (CF) patients. Our model suggests control strategies where the activities of the enzyme PIP5KI or the PI4K+PIP5KI+DVL protein complex are decreased and cause an efficacious reduction in PI(4,5)P2levels while avoiding undesirable alterations in other phosphoinositide pools.AbbreviationsAKTProtein Kinase B, a serine/threonine-specific protein kinaseASLAirway surface liquidBSTBiochemical systems theoryCFCystic fibrosisDAGDiacylglycerolENaCEpithelial Sodium ChannelEREndoplasmic ReticulumGMAGeneralized mass actionINPP5Inositol polyphosphate 5-phosphatasesIP3Inositol triphosphateLTPslipid transport proteinsMCSsmembrane contact sitesMDCK cellsMadin-Darby Canine Kidney Epithelial CellsMTMMyotubularinOCRLLowe Oculocerebrorenal Syndrome Protein; OCRL is an INPP5ODEOrdinary differential equationsPIPhosphatidylinositolPI(3)Pphosphatidylinositol 3-phosphatePI(3,4)P2Phosphatidylinositol 3,4-biphosphatePI(3,4,5)P3phosphatidylinositol 3,4,5-triphosphate, with phosphates in the third, fourth and fifth positionsPI(3,5)P2Phosphatidylinositol 3,5-biphosphatePI(4)Pphosphatidylinositol 4-phosphatePI(4,5)P2Phosphatidylinositol 4,5-biphosphate with phosphates in the fourth and fifth positions of the inositol ringPI(5)Pphosphatidylinositol 5-phosphatePI3KPhosphoinositide 3-kinasePI4KPhosphoinositide 4-kinasePIP5KPhosphoinositide 4-phosphate 5-kinasePIKfyveFYVE finger-containing phosphoinositide kinase.PLCPhospholipase CPLDPhospholipase DPLIPPTEN-like lipid phosphatasePTENPhosphatase and tensin homologPKCProtein kinase CSACSuppressor of actinSHIP1SH2 domain-containing phosphatidylinositol 5’-phosphataseSKIPSkeletal muscle and kidney enriched inositol polyphosphate phosphataseSYNJSynaptojaninsTPIPPTEN-Like Inositol Lipid PhosphataseWnt3aWingless-Type MMTV Integration Site Family, Member 3ADVLSegment Polarity Protein Dishevelled Homolog DVL

Early signalling events of autophagy

2013 ◽  
Vol 55 ◽  
pp. 1-15 ◽  
Author(s):  
Laura E. Gallagher ◽  
Edmond Y.W. Chan
Keyword(s):  
Protein Kinase ◽  
Focal Adhesion Kinase ◽  
Focal Adhesion ◽  
Mammalian Cells ◽  
Mammalian Target Of Rapamycin ◽  
Interacting Protein ◽  
The Core ◽  
Autophagy Gene ◽  
Autophagy Induction ◽  
Cellular Pathways

Autophagy is a conserved cellular degradative process important for cellular homoeostasis and survival. An early committal step during the initiation of autophagy requires the actions of a protein kinase called ATG1 (autophagy gene 1). In mammalian cells, ATG1 is represented by ULK1 (uncoordinated-51-like kinase 1), which relies on its essential regulatory cofactors mATG13, FIP200 (focal adhesion kinase family-interacting protein 200 kDa) and ATG101. Much evidence indicates that mTORC1 [mechanistic (also known as mammalian) target of rapamycin complex 1] signals downstream to the ULK1 complex to negatively regulate autophagy. In this chapter, we discuss our understanding on how the mTORC1–ULK1 signalling axis drives the initial steps of autophagy induction. We conclude with a summary of our growing appreciation of the additional cellular pathways that interconnect with the core mTORC1–ULK1 signalling module.

scholarly journals Control of PKR Protein Kinase by Hepatitis C Virus Nonstructural 5A Protein: Molecular Mechanisms of Kinase Regulation

1998 ◽  
Vol 18 (9) ◽  
pp. 5208-5218 ◽  
Author(s):  
Michael Gale ◽  
Collin M. Blakely ◽  
Bart Kwieciszewski ◽  
Seng-Lai Tan ◽  
Michelle Dossett ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Protein Kinase ◽  
Mammalian Cells ◽  
Molecular Mechanisms ◽  
Functional Assay ◽  
Binding Region ◽  
Dimerization Domain ◽  
Antiviral Effects

ABSTRACT The PKR protein kinase is a critical component of the cellular antiviral and antiproliferative responses induced by interferons. Recent evidence indicates that the nonstructural 5A (NS5A) protein of hepatitis C virus (HCV) can repress PKR function in vivo, possibly allowing HCV to escape the antiviral effects of interferon. NS5A presents a unique tool by which to study the molecular mechanisms of PKR regulation in that mutations within a region of NS5A, termed the interferon sensitivity-determining region (ISDR), are associated with sensitivity of HCV to the antiviral effects of interferon. In this study, we investigated the mechanisms of NS5A-mediated PKR regulation and the effect of ISDR mutations on this regulatory process. We observed that the NS5A ISDR, though necessary, was not sufficient for PKR interactions; we found that an additional 26 amino acids (aa) carboxyl to the ISDR were required for NS5A-PKR complex formation. Conversely, we localized NS5A binding to within PKR aa 244 to 296, recently recognized as a PKR dimerization domain. Consistent with this observation, we found that NS5A from interferon-resistant HCV genotype 1b disrupted kinase dimerization in vivo. NS5A-mediated disruption of PKR dimerization resulted in repression of PKR function and inhibition of PKR-mediated eIF-2α phosphorylation. Introduction of multiple ISDR mutations abrogated the ability of NS5A to bind to PKR in mammalian cells and to inhibit PKR in a yeast functional assay. These results indicate that mutations within the PKR-binding region of NS5A, including those within the ISDR, can disrupt the NS5A-PKR interaction, possibly rendering HCV sensitive to the antiviral effects of interferon. We propose a model of PKR regulation by NS5A which may have implications for therapeutic strategies against HCV.

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