Chemistry of Life

Molecular genetics, biochemistry

PIPs

Phosphatidylinositolpolyphosphates (PIPs) are centrally involved in many biological processes, ranging from cell growth and organization of the actin cytoskeleton to endo- and exocytosis.

▼: actin : ADP-ribosylation factor (ARF) : DAG : diacylglycerols : diacylglycerol second messenger : diacylglycerol kinases : DGKs : eicosanoids : CDP-diacylglycerol : fibronectin : hexahydroxycyclohexane : inositol : inositol phospholipids : InsP3 : IP3 : Kit-ligand : PDGF receptor : phosphatidic acid, PA : phosphatidylinositol : phosphatidylinositol phosphates : phospholipase A2 : phospholipase C family : phospolipase C-γ : PI3K : PI3K ARF : PI3K cancer : PI3K Kit : PI3K signaling : PLC-γ : polyphosphoinositides : prostaglandins : ▼

Phosphatidylinositol is an important lipid, both as a participant in essential metabolic processes and as a key membrane constituent. In addition to their role as negatively charged building blocks of membranes, the inositol phospolipids (including the phosphatidylinositol phosphates, sometimes termed 'polyphosphoinositides', appear to have crucial roles in interfacial binding of proteins and in the regulation of proteins at the cell interface. The are particularly effective in specific binding to PH domains of cellular proteins.

Phosphatidylinositol is especially abundant in brain tissue, where it can amount to 10% of the phospholipids, and it is found in all plants and animals (and in some bacteria such as actinomycetes). Phosphatidylinositol is an acidic (anionic) phospholipid comprising a phosphatidic acid backbone, linked via the phosphate group to inositol (hexahydroxycyclohexane). Phosphatidylinositol is formed biosynthetically (usually in the endoplasmic reticulum) from the precursor CDP-diacylglycerol by reaction with inositol, in a reaction catalysed by the enzyme CDP-diacylglycerol inositol phosphatidyltransferase.

Phosphatidylinositol is the primary source, in animal tissues of the arachidonic acid required for biosynthesis of eicosanoids, including prostaglandins, via the action of the enzyme phospholipase A2, which releases the fatty acids from position sn-2. Phospholipases are enzymes that hydrolyze specific ester bonds in phosphoglycerides or glycerophosphatidates, converting the phospholipids into fatty acids and other lipophilic substances. Phospholipases are involved in signaling cascades. Most importantly, phosphatidylinositol and the phosphatidylinositol phosphates provide the main source of diacylglycerols (sn-1,2-diacylglycerols) that function as second messenger, signaling molecules in plant and animal cells. The hydrolysis is catalysed by the highly specific phospholipase C family.

Activation of the phospolipase, PLC-γ results in hydrolysis of membrane phosphatidylinositol bisphosphate (PIP2), which leads to an elevation of intracellular second messengers, diacylglycerol (DAG) and inositol trisphosphate (IP3, InsP3), which interact with intracellular membrane receptors to effect release of stored calcium ions (PKC is maximally active in the presence of calcium ion and diacylglycerol).

Diacylglycerol (DAG) is an intracellular second messenger that remains attached to the inner membrane. DAG accumulates transiently in cells exposed to growth factors or other stimuli. Cellular responses such as growth and differentiation are impacted by the binding of DAG to PKC, the action of which requires calcium ions generated by inositol-1,4,5-trisphosphate (IP3, InsP3). Diacylglycerol kinases (DGKs) are responsible for eliminating the function of diacylglycerol (DAG) and for producing phosphatidic acid (PA) (both molecules are connected to cancer).

The phosphatidylinositide-3-OH kinase (PI3K)/3-phosphoinositide-dependent protein kinase-1 (PDK1)/Akt and the Raf/mitogen-activated protein kinase (MAPK/ERK) kinase (MEK)/mitogen-activated protein kinase (MAPK) pathways play central roles in the regulation of survival and proliferation of cells.

Phosphatidylinositide-3' (PI 3)-kinase participates in Kit-ligand (KL)-induced adhesion of bone marrow-derived mast cells (BMMCs) to fibronectin. The Kit receptor tyrosine kinase is a member of the PDGF receptor subfamily that mediates diverse responses including proliferation, survival, chemotaxis, migration, differentiation, and adhesion to extracellular matrix. PKCs play a dual role as both positive and negative regulators of Kit function by acting as downstream mediators in addition to participating in a negative feedback loop that down-regulates Kit receptor activity. PKC is activated by diacylgylcerol and by products of PI-3 kinase. Kit participates in the secretion of inflammatory mediators in connective tissue mast cells. Receptor-proximal PI 3-kinase activation and activation of a PKC isoform appear to have a role in Kit-mediated secretory enhancement, adhesion, and cytoskeletal reorganization.[r]

Agonist stimulation of phosphatidylinositide 3-kinase (PI 3-kinase) activates a pathway that leads to activation of ADP-ribosylation factor (ARF) 6, which regulates plasma membrane trafficking and cortical actin formation by cycling between inactive GDP and active GTP-bound conformations.

Components of the Ras and PI(3)K signalling pathways are mutated in most human cancers. The high frequency of mutations in these pathways suggests that the loss of growth-control checkpoints and the promotion of cell survival in nutrient-limited conditions may be an obligate event in carcinogenesis.[r]

▲: actin : ADP-ribosylation factor (ARF) סּ cell membranescytoskeleton : DAG : diacylglycerols : diacylglycerol second messenger : diacylglycerol kinases : DGKs : eicosanoids : CDP-diacylglycerol : fibronectin : hexahydroxycyclohexane : inositol : inositol phospholipids : InsP3 : IP3 : Kit-ligand : PDGF receptor : phosphatidic acid, PA : phosphatidylinositol : phosphatidylinositol phosphates : phospholipase A2 : phospholipase C family : phospolipase C-γPI3K : PI3K : PI3K ARF : PI3K cancer : PI3K Kit : PI3K signaling : PLC-γ : polyphosphoinositides : prostaglandins ~ second messengers ¤ signaling moleculessignal transductiontransport : ▲

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. . . transcription begun 10/06/06