Lipid signaling

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Lipid signaling refers to a number of cellular signal transduction pathways that use cell membrane lipids as second messengers. Most of the lipids of the plasma membrane play an exclusively structural role. However, a small proportion of them are involved in relaying extracellular stimuli into the cell. The best studied of these pathways centres around diacylglycerol(DAG) and inositol triphosphate(IP3), which is described in detail in this article. Ceramide lipids also play in cell signaling.

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[edit] Function

Lipid signaling pathways are activated by a variety of extracellular stimuli ranging from growth factors to inflamatory cytokines. They regulate cell fate decisions such as apoptosis, differentiation and proliferation. Lipid signaling can play a major role in carcinogenesis, the development of cancer. Phorbol esters mimic the lipid second messenger diacylglycerol and can stimulate cancer cells to divide.

[edit] Mechanism

The key event of lipid signaling is the hydrolysis of Phosphatidylinositol (4,5)-bisphosphate(PIP2) to diacylglycerol(DAG) and inositol triphosphate(IP3) by the phospholipase C (PLC) enzyme. Two PLC isoforms, PLC-β activated by G proteins, and, PLC-γ activated by receptor tyrosine kinases, catalyse this reaction.

IP3 is soluble and diffuse freely into the cytoplasm. It is recognised by the inositol triphosphate receptor(IP3R), a Ca2+ channel in the endoplasmic reticulum(ER) membrane. The ER acts as intracellular Ca2+ store. The binding of IP3 to IP3R releases the flow of calcium from the ER into the normally Ca2+-poor cytoplasm, which then triggers various events of calcium signaling. Ca2+ binds the protein calmodulin, which regulates a range of cellular targets, such as the Ca2+/calmodulin-dependent protein kinases. Intracellular Ca2+ is also essential for activation of conventional Protein kinase C isoforms. DAG remains bound to the membrane by its fatty acid "tails". Their it recruits and activates both conventional and novel members of the Protein kinase C family. Thus, both IP3 and DAG contribute to activation of PKCs.

Protein kinase C-α is a conventional PKC and requires both DAG and Ca2+ for activity. One of the targets activated by PKC-α is phospholipase D, which hydrolyses phosphatidylcholine(PC) to choline and phosphatidic acid. The latter is rapidly converted to DAG. PC-derived DAG can be distinguished from PIP2-derived as their differ in their fatty acid composition. PC forms the bulk of the lipids of the plasma membrane and provides an inexhaustible supply of substrates for PLD. DAG produces through this mechanism may continue to activate PKC hours after the initial extracellular stimulus.

[edit] References

[edit] General reviews

  • Irvine RF (1992). "Inositol lipids in cell signalling". Curr Opin Cell Biol 4 (2): 212-219. Entrez PubMed 1318060
  • Nishizuka Y (1995). "Protein kinase C and lipid signaling for sustained cellular responses". FASEB J 9 (7): 484-496. Entrez PubMed 7737456


Lipid signaling
Phospholipase | Phosphatidylinositol (4,5)-bisphosphate | Diacylglycerol | Inositol triphosphate | Inositol triphosphate receptor


Cell signaling
Key concepts    - Ligand | Receptor | Second messenger | Protein kinase | Transcription factor | Cell signaling networks
Pathways    - Apoptosis | Ca2+ signaling | Cytokine signaling | Hedgehog | Integrin signaling | JAK/STAT | Lipid signaling | MAPK/ERK pathway | mTOR | NF-kB | Notch | p53 | TGFβ | Wnt
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