Fig. 7.17 Phospholipase C-γ cleaves inositol phospholipids to generate two important signaling molecules. Top panel: phosphatidylinositol bisphosphate (pip2) is a component of the inner leaflet of the plasma membrane. When pLc-γ is activated by phosphorylation, it cleaves pip2 into two parts: inositol trisphosphate (ip3), which diffuses away from the membrane into the cytosol, and diacylglycerol (daG), which stays in the membrane. Both of these molecules are important in signaling. middle panel: there are two phases of calcium release. ip3 binds to a receptor in the endoplasmic reticulum (eR) membrane, opening calcium channels (yellow) and allowing the early phase of calcium ions (ca2+) to enter the cytosol from the eR. The depletion of ca2+ stores in the eR causes the aggregation of an eR calcium sensor, STim1. Bottom panel: aggregated STim1 stimulates the second phase of calcium entry by binding to and opening calcium channels called oRai1 in the plasma membrane. This further increases cytosolic calcium and restores eR ca2+ stores. daG binds and recruits signaling proteins to the membrane, most importantly the Ras-Gef called RasGRp and a serine/threonine kinase called protein kinase c-θ (pKc-θ). Recruitment of RasGRp to the plasma membrane activates Ras, and pKc-θ activation results in the activation of the transcription factor nfκB.
Left panel: nfaT is maintained in the cytoplasm by phosphorylation on serine and threonine residues. center panel: after antigen receptor stimulation, calcium enters the cytosol, first from the endoplasmic reticulum (not shown; see fig. 7.17) and later from the extracellular space (shown). after entering the cytosol, calcium binds to calmodulin, and the ca2+:calmodulin complex binds to the serine/threonine phosphatase calcineurin, activating it to dephosphorylate nfaT. Right panel: once dephosphorylated, nfaT moves into the nucleus, where it binds to promoter elements and activates the transcription of various genes.
MOVIE 7.2 signals, NFAT is kept in the cytosol of resting T cells by phosphorylation on serine/threonine residues. This phosphorylation is mediated by serine/threonine kinases, including glycogen synthase kinase 3 (GSK3) and casein kinase 2 (CK2). When phosphorylated, the nuclear localization sequence of NFAT is not recognized by nuclear transporters, and NFAT is unable to enter into the nucleus (Fig. 7.18).
The cytoplasmic Ca2+ resulting from T-cell receptor signaling binds to and induces a conformational change in a protein called calmodulin, which is then able to bind to and activate a wide range of different target enzymes. In T cells, an important target of calmodulin is calcineurin, a protein phosphatase that acts on NFAT. Dephosphorylation of NFAT by calcineurin allows the nuclear localization sequence to be recognized by nuclear transporters, and NFAT enters the nucleus (see Fig. 7.18). There it participates in turning on many of the genes crucial for T-cell activation, such as the gene for the cytokine interleukin-2 (IL-2).