The calcium pathway

The activation of the TCR-associated tyrosine kinases is followed within 15 s by the activation of another enzyme, phospholipase C (PLC), which may be activated by phosphorylation on tyrosine residues. Activation of PLC is accompanied by binding of a 36 kDa protein which may have a role as an adapter protein in localizing PLC to the cell membrane. PLC;

Has pathways

Calcium PKC

pathways pathways

Has pathways

Calcium PKC

pathways pathways

Figure 2 Signaling complexes and pathways associated with the T cell antigen receptor (TCR). The eight chain TCR and the CD4 and CD45 coreceptors are shown with associated kinases Ick, fyn and ZAP 70. There are 10 ITAM motifs encoded in the TCR subunits. Tyrosine kinase activation results in the phosphorylation of a number of substrates, including phospho-lipase C (PLC). Activation of PLC results in increased calcium concentration and protein kinase C (PKC) activity. Tyrosine kinase activation also leads to activation of Ras via several mechanisms. mSOS, mammalian Son of Sevenless; GRB-2, growth factor receptor-bound protein 2; IP3R, inositol triphosphate receptor; SHP-1, SH2-containing tyrosine phosphatase 1; pyK2, proline-rich tyrosine kinase 2

cleaves a membrane phospholipid, phosphatidyl-inositol 4,5-biphosphate (PIP2) into a cyclitol polyphosphate, inositol, 1,4,5-triphosphate (IP,) and a diacylglycerol, (DAG). Both of these enzymatic products function in the subsequent steps of the signal transduction cascade. IP, is the ligand which operates a receptor, located in the endoplasmic reticulum and plasma membrane, to release a nonmito-chondrial, ATP-dependent store of ionized calcium. In some T cells, the IP, receptor is a substrate of the TCR-associated p59^'" tyrosine kinase. As a result of the actions of IP, the concentration of intracellular calcium ion rises briefly from resting levels of 0.1 p.M to 0.5 |LiM or higher. Calcium activates the serine/threonine phosphatase calcineurin. One target of calcineurin is NFATp, a transcription factor that has a role in IL-2 gene expression. Calcium has many roles in cellular homeostasis and cell activation, and it is clear that calcium-mediated signaling pathways that are both calcineurin dependent and independent, exist in T cells. Several reports have indicated that isolated cytosolic free calcium elevations in T cells tend to provoke apoptosis or anergy. This can occur by apparently independent mechanisms involving alterations of TCR signaling, by the absence of costimulatory signaling or by treatment of cells with calcium ionophore.

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