Fig. 7.19 DAG activates MAPK cascades, leading to transcription factor activation. all mapK cascades are initiated by the activation of small G proteins, such as Ras in this example. Ras is switched from an inactive state (first panel) to an active state (second panel) by a guanine-nucleotide exchange factor (Gef), RasGRp, which is recruited to the membrane by daG. Ras activates the first enzyme of the cascade, a protein kinase called Raf, a mapK kinase kinase (map3K) (third panel). Raf phosphorylates mek, a map2K, which in turn phosphorylates and activates erk, a mapK. The scaffold protein KSR associates with Raf, mek, and erk to facilitate their efficient interactions (not shown). phosphorylation and activation of erk releases it from the complex so that it can diffuse within the cell and enter the nucleus (fourth panel). phosphorylation of transcription factors by erk results in new gene transcription.
Fig. 7.20 The transcription factor AP-1 is formed as a result of the Ras/ MAPK signaling pathway. Left panel: phosphorylation of the mapK erk activated as a result of the Ras–mapK cascade allows erk to enter the nucleus, where it phosphorylates the transcription factor elk-1. elk-1, along with serum response factor (SRf), binds to the serum response element (SRe) in the promoter of the gene (FOS) for the transcription factor c-fos, stimulating its transcription. Right panel: the protein kinase pKc-θ can induce the phosphorylation of another mapK called Jun kinase (JnK). This enables JnK to enter the nucleus and phosphorylate the transcription factor c-Jun, which forms a dimer with c-fos. The phosphorylated c-Jun/fos dimer is an active ap-1 transcription factor that binds to ap-1 sites and promotes transcription of many target genes.
cooperates with a transcription factor called serum response factor to initiate transcription of the FOS gene. Fos protein then associates with Jun to form the AP-1 heterodimer, but this remains transcriptionally inactive until another MAPK called Jun kinase (JNK) phosphorylates Jun. Similar to NFAT, AP-1 participates in turning on transcription of many genes important for T-cell activation, including the gene encoding the cytokine IL-2.
7-16 Protein kinase C activates the transcription factors NFκB and AP-1.
The third signaling pathway leading from PLC-γ results in the activation of PKC-θ, an isoform of protein kinase C that is restricted to T cells and muscle. Mice lacking PKC-θ develop T cells in the thymus, but their mature T cells have a defect in the activation of two crucial transcription factors, NFκB and AP-1, in response to signaling by the T-cell receptor and CD28. These transcription factors also participate in turning on genes required for T-cell activation. For example, transcription of the gene for IL-2 requires NFκB in addition to NFAT and AP-1, making PKC-θ activation an important component of T-cell activation.
PKC-θ has a C1 domain and is recruited to the membrane when DAG is generated by activated PLC-γ (see Fig. 7.17). In this location, the kinase activity of PKC-θ initiates a series of steps that results in the activation of NFκB (Fig. 7.21). PKC-θ phosphorylates the large membrane-localized scaffold protein CARMA1, causing it to oligomerize and form a multisubunit complex with other proteins. This complex recruits and activates TRAF-6, the same protein that we encountered in Chapter 3 in its role in activating NFκB in the TLR signaling pathway (see Fig. 3.13).