286 PART Il Immune Effector Mechanisms the transcription of specific genes. While docked to receptor subunits, STATs undergo JAK-catalyzed Dimerization phosphorylation of a key tyrosine. This is followed by the dissociation of the STATs from the receptor subunits and their dimerization the stat dimers then translocate into the nucleus and induce the expression of genes containing appropriate regulatory sequences in their promoter regions PrEaCtivation of JAK In addition to ifn- and their receptors. Another aspect of cytokine specificity is that each particular cytokine (or group of redundant cyto- kines)induces transcription of a specific subset of genes in cO Dimerization given cell type; the resulting gene products then mediate the of stat various effects typical of that cytokine. The specificity of cytokine effects is then traceable to three factors. First, pa ticular cytokine receptors start particular JAK-STAT path ways. Second, the transcriptional activity of activated STaTs DNAOXXXXXXXXXC ecific gene transcription 12-10 General model of signal transduction mediated by most class I and class ll cytokine receptors. Binding of a cytokine in duces dimerization of the receptor subunits, which leads to the activa- tion of receptor-subunit-associated JAK tyrosine kinases by reciprocal phosphorylation. Subsequently, the activated JAKs phosphorylate var ous tyrosine residues, resulting in the creation of docking sites fo STATs on the receptor and the activation of the one or more STAT tran cription factors. The phosphorylated STATs dimerize and translocate to the nucleus, where they activate transcription of specific genes complex. Members of a family of transcription factors known as stats(signal transducers and activators of transcription) bind to these phosphorylated tyrosine residues Specific STATs(see Table 12-2) play essential roles in the signaling pathways of a wide variety of cytokines. The binding of STATS to receptor subunits is FIGURE 12.11 The complex between IFN-y and the ligand-binding mediated by the joining of the sh2 domain on the chains of its receptor. This model is based on the x-ray crystallo- STAT with the docking site created by the JAK-mediated blue)bound to ligand-binding a chains of the receptor (green and yellow). Note that IFN-y is shown in its native dimeric form; each member of the dimer engages the a chain of an IFN-y receptor, After undergoing JAK-Imediated phosphorylation, STAT thereby bringing about receptor dimerization and signal transduc- transcription factors translocate from receptor docking tion / From M.R. Walter et al., 1995, Nature 376: 230, courtesy M. Walter, tes at the membrane to the nucleus, where they initiate University of Alabama.complex. Members of a family of transcription factors known as STATs (signal transducers and activators of transcription) bind to these phosphorylated tyrosine residues. Specific STATs (see Table 12-2) play essential roles in the signaling pathways of a wide variety of cytokines. The binding of STATs to receptor subunits is mediated by the joining of the SH2 domain on the STAT with the docking site created by the JAK-mediated phosphorylation of a particular tyrosine on receptor subunits. ■ After undergoing JAK-mediated phosphorylation, STAT transcription factors translocate from receptor docking sites at the membrane to the nucleus, where they initiate the transcription of specific genes. While docked to receptor subunits, STATs undergo JAK-catalyzed phosphorylation of a key tyrosine. This is followed by the dissociation of the STATs from the receptor subunits and their dimerization. The STAT dimers then translocate into the nucleus and induce the expression of genes containing appropriate regulatory sequences in their promoter regions. In addition to IFN-, a number of other class I and class II ligands have been shown to cause dimerization of their re￾ceptors. An important element of cytokine specificity derives from the exquisite specificity of the match between cytokines and their receptors. Another aspect of cytokine specificity is that each particular cytokine (or group of redundant cyto￾kines) induces transcription of a specific subset of genes in a given cell type; the resulting gene products then mediate the various effects typical of that cytokine. The specificity of cytokine effects is then traceable to three factors. First, par￾ticular cytokine receptors start particular JAK-STAT path￾ways. Second, the transcriptional activity of activated STATs 286 PART III Immune Effector Mechanisms α β α β Dimerization of receptor Activation of JAK family tyrosine kinases, phosphorylation of receptor Tyrosine phosphorylation of STAT by JAK kinase Dimerization of STAT DNA Specific gene transcription P P P P P P P P P P STAT SH2 JAK Cytokine FIGURE 12-10 General model of signal transduction mediated by most class I and class II cytokine receptors. Binding of a cytokine in￾duces dimerization of the receptor subunits, which leads to the activa￾tion of receptor-subunit-associated JAK tyrosine kinases by reciprocal phosphorylation. Subsequently, the activated JAKs phosphorylate vari￾ous tyrosine residues, resulting in the creation of docking sites for STATs on the receptor and the activation of the one or more STAT tran￾scription factors. The phosphorylated STATs dimerize and translocate to the nucleus, where they activate transcription of specific genes. FIGURE 12-11 The complex between IFN- and the ligand-binding chains of its receptor. This model is based on the x-ray crystallo￾graphic analysis of a crystalline complex of interferon- (violet and blue) bound to ligand-binding chains of the receptor (green and yellow). Note that IFN- is shown in its native dimeric form; each member of the dimer engages the chain of an IFN- receptor, thereby bringing about receptor dimerization and signal transduc￾tion. [From M. R. Walter et al., 1995, Nature 376:230, courtesy M. Walter, University of Alabama.]