8536dch10221-2478/29/022:31 PM Page232mac14Mac114:2 shift:1268tm:8536a VISUALIZING CONCEPT Engagement of MHC'peptide initiates processes that lead to assembly of signaling complex. Class II MHC Yδ∈ CD4/8-associated Lck phosphorylates ITAMs of coreceptors, creates docking site for ZAP-70 DAG PkC-mediated pathways ZAP-70 Ca-mediated pathways → Small G-protein- SLP-76 mediated pathways LAT Ras Pathway Rac Pathway PLCY Changes in gene expression GADS LAT · Functional changes Differentiation Activation ZAP-70 phosphorylates adaptor molecules that recruit components of several signaling pathways FIGURE Overview of TCR-mediated signaling TCR en- Grb2-like adaptor downstream of Shc; GEF= guanine nucleotide gagement by peptide-MHC complexes initiates the assembly of a exchange factor, ITAM= immunoreceptor tyrosine- based activa- signaling complex. An early step is the Lck-mediated phosphory. tion motif, Itk= inducible T cell kinase; IP3= inositol 1, 4, 5 lation of ITAMs on the zeta(s)chains of the TCR complex, creat- triphosphate; LAT linker of activated T cells; PIP2= phospho- ing docking sites to which the protein kinase ZAP-70 attaches inositol biphosphage: PLCy= phospholipase C gamma; Lck and becomes activated by phosphorylation. A series of ZAP-70- lymphocyte kinase; SLP-76= SH2-containing leukocyte-specific atalyzed protein phosphorylations enable the generation of a protein of 76 kDa; ZAP-70= zeta associated protein of 70 k Da. variety of signals (Abbreviations: DAG= diacylglycerol: GADSVISUALIZING CONCEPTS FIGURE 10-10 Overview of TCR-mediated signaling. TCR en￾gagement by peptide-MHC complexes initiates the assembly of a signaling complex. An early step is the Lck-mediated phosphory￾lation of ITAMs on the zeta () chains of the TCR complex, creat￾ing docking sites to which the protein kinase ZAP-70 attaches and becomes activated by phosphorylation. A series of ZAP-70- catalyzed protein phosphorylations enable the generation of a variety of signals. (Abbreviations: DAG = diacylglycerol; GADS = Grb2-like adaptor downstream of Shc; GEF = guanine nucleotide exchange factor; ITAM = immunoreceptor tyrosine-based activa￾tion motif; Itk = inducible T cell kinase; IP3 = inositol 1,4,5 triphosphate; LAT = linker of activated T cells; PIP2 = phospho￾inositol biphosphage; PLC = phospholipase C gamma; Lck = lymphocyte kinase; SLP-76 = SH2-containing leukocyte-specific protein of 76 kDa; ZAP-70 = zeta associated protein of 70 kDa.) 1 Engagement of MHC-peptide initiates processes that lead to assembly of signaling complex. CD4/8-associated Lck phosphorylates ITAMs of coreceptors, creates docking site for ZAP-70 3 ZAP-70 phosphorylates adaptor molecules that recruit components of several signaling pathways ζ ζ γ δ  Class II MHC Peptide CD4/8 TCR P P P P P P P P P Lck ZAP-70 SLP-76 LAT GADS LAT SLP67 ItK PLCγ GEF DAG PIP2 IP3 PkC-mediated pathways CA2+-mediated pathways Small G-protein— mediated pathways • Ras Pathway • Rac Pathway • Changes in gene expression • Functional changes • Differentiation • Activation 2 8536d_ch10_221-247 8/29/02 2:31 PM Page 232 mac114 Mac 114:2nd shift:1268_tm:8536d: