Phospholipase C Signaling

The phospholipase c (PLC) family is divided into six classes: PLC-β, PLC-γ, PLC-δ, PLC-ε, PLC-ζ and PLC-η. PLC-β is activated by the G-αQ or G-β γ subunits released from heterotrimeric G-proteins after ligand stimulation. They are also activated by Rac. PLC-γ, on the other hand, is activated by receptor or non-receptor tyrosine kinases. Polypeptide growth factors activate PLC-γ1 in a wide variety of cells. PLC-γ is also activated by BCR, TCR, the high affinity IgE receptor and the IgG receptors.Ligation of TCR triggers the activation of Lck and Fyn followed by ZAP70. These proteins, then phosphorylate various downstream substrates including membrane bound LAT and ITK bound SLP76, eventually activating PLC-γ1. BCR engagement triggers the activation of Lyn followed by SYK which phosphorylates BLNK thereby inducing its translocation to the cell membrane. BLNK contributes to activation of BTK and PLC-γ. SYK also directly activates PLC-γ. Ligation of Fc receptors to soluble Ig and immune complexes also contributes to PLC-γ activation.Src is responsible for the activation of PLC-γ in vascular smooth muscle cells and platelets. Phosphatidic acid is an immediate product of phosphatidylcholine hydrolysis by PLD, activation of which results in the activation of PLC-γ. Arachidonic acid stimulates PLC-γ activity independent of tyrosine phosphorylation in the presence of Tau. Activation PLC-γ is also activated by integrins via Src.PLC-δ activation involves increases in intracellular Ca2+ concentrations. Ral, a small GTPase, promotes PLC-δ activity. Calmodulin binds and inhibits PLC-δ activity and Ral can reverse this inhibition. PLC-ε is an effector of Ras and Rap. These activated GTPases directly stimulate PLC-ε. The phospholipase activity of PLC-ε is also enhanced through direct interaction with GTP-RhoA. PLC-η has an important role postnatally in the brain. In neurons, PLC-η functions as a Ca2+ sensor that is activated by small increases in intracellular Ca2+ concentrations under physiological conditions.Activation of PLC results in the hydrolysis of PIP2 to release the second messengers DAG and IP3. DAG is the physiological activator of PKC and IP3 stimulates release of stored Ca2+ from the ER. Ca2+ release activates Calm which further activates Calcineurin, CamKKs and CamKs. Calneurin facilitates NFAT translocation to the nucleus, a process that is essential for axonal growth.PKC phosphorylates CPI17. Phosphorylation of CPI17 enhances its ability to bind to the catalytic subunit of MLCP causing inhibition of MLCP activity and MLC phosphorylation that leads to actomyosin assembly contraction. PKC phosphorylates transcription factors such as NF-κB, regulating the transcription of certain genes thus controlling cell proliferation or apoptosis. PKC also phosphorylates MARCKS in response to integrin signaling, which is involved in the reorganization of the actin cytoskeleton. PKCs also activate the ERK cascade, including direct phosphorylation of Raf1.