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Phosphoinositide (Lipid) Signaling

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Phosphoinositide (Lipid) Signaling

Pathway Description:

Phosphatidylinositol (PtdIns) is a small lipid molecule composed of an inositol ring and two fatty acid chains connected through a glycerol backbone, a structure that allows PtdIns to anchor on the cytoplasmic face of cellular membranes. PtdIns is phosphorylated by a host of lipid kinases at the 3, 4, and/or 5 hydroxyl positions of the inositol ring, producing a variety of phosphatidylinositol monophosphates (PI3P, PI4P, and PI5P), diphosphates [PI(3,4)P2, PI(3,5)P2, PI(4,5)P2], and a triphosphate [PI(3,4,5)P3] that are collectively known as phosphoinositides. The phosphorylations are removed by site-specific lipid phosphatases, enabling dynamic flux between lipid phosphorylation states. In general, phosphatidylinositol monophosphates are localized to intracellular membranes (endocytic vesicles, golgi apparatus, nucleus), while di- and triphosphates are found at the plasma membrane. PtdIns (synthesized at the endoplasmic reticulum) and phosphoinositides shuttle among various subcellular compartments by intracellular vesicles that enable association with their corresponding modifying enzymes. Phosphoinositides are universal signaling entities that regulate cell activities through direct interaction with membrane proteins (e.g., ion channels, GPCRs) or through membrane recruitment of cytosolic proteins containing domains that directly bind phosphoinositides, such as pleckstrin homology (PH), FYVE, WD40 repeats, FERM, PTB, and PDZ domains, among others. By far the best studied phosphoinositide is PI(3,4,5)P3, which is synthesized from PI(4,5)P2 by PI3K Class I and dephosphorylated by PTEN. Both PI3K Class I and PTEN are central mediators of receptor tyrosine kinase-induced Akt signaling, and are often mutated in many forms of cancer. In addition to its effect on cell proliferation, survival, and metabolism associated with Akt signaling, phosphoinositide signaling also induces cytoskeletal changes and actin remodeling, and plays a role in clathrin-mediated endocytosis, vesicle trafficking, membrane dynamics, autophagy, cell division/cytokinesis, cell migration, and UV stress response.

Selected Reviews:

created August 2017
Acetylase
Acetylase
Metabolic Enzyme
Metabolic Enzyme
Adaptor
Adaptor
Methyltransferase or G-protein
Methyltransferase or G-protein
Adaptor
Apoptosis/Autophagy Regulator
Phosphatase
Phosphatase
Cell Cycle Regulator
Cell Cycle Regulator
Protein Complex
Protein Complex
Deacetylase or Cytoskeletal Protein
Deacetylase or Cytoskeletal Protein
Ubiquitin/SUMO Ligase or Deubiquitinase
Ubiquitin/SUMO Ligase or Deubiquitinase
Growth Factor/Cytokine/Development Protein
Growth Factor/Cytokine/Development Protein
Transcription Factor or Translation Factor
Transcription Factor or Translation Factor
GTPase/GAP/GEF
GTPase/GAP/GEF
Receptor
Receptor
Kinase
Kinase
Other
Other
 
Direct Process
Direct Process
Tentative Process
Tentative Process
Translocation Process
Translocation Process
Stimulatory Modification
Stimulatory Modification
Inhibitory Modification
Inhibitory Modification
Transcriptional Modification
Transcriptional Modification
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