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1、Signal Transduction,Prof. Tianhua Zhou,Department of Cell Biology Zhejiang University School of Medicine,Office hours by appointment ,Part II,Diversity, Receptors, GTPase switch proteins, protein kinases, adaptor proteins, protein phosphatases,A. Cell-surface receptor pathways (receptors that are Io
2、n channels, Signaling through G-protein-coupled receptors, Signaling through Enzyme-linked receptors, Signaling that involved in proteolysis),B. Intracellular receptor pathways (Nitric oxide pathway, Nuclear receptor pathway),I. Signaling molecules:,II. Signaling Pathways:,B. The adaptation of targe
3、ting cells: Receptor sequestration, down-regulation, inactivation, Production of inhibitory protein, Inactivation of signaling protein,III. The regulation of cell signaling:,A. The interaction between different signaling pathways (Convergence, Divergence, Crosstalk),Key contents for signal transduct
4、ion:,The major signaling pathways activated by GPCRs and RTKs,Signal Molecule,G-protein coupled receptor,Receptor tyrosine receptor,G protein,G protein,Adenylyl cyclase,cAMP,PKA,Gene regulatory proteins,CaM Kinase,PKC,MAPK,PKB,Many target proteins,PLC,IP3,DAG,Calmodulin,Ca2+,Grb2,Ras-GEF,Ras,MAPKKK,
5、MAPKK,PI-3 kinase,PI(3,4,5)P3,PDK1,3.2 Cytokine receptors pathway,Ligands: Interferons, erythropoitin (EPO), some interleukins (IL-2, IL-4) and others.,Receptors: Single transmembrane a helix; JAK kinase associated with intracellular domain.,Signal transduction:,Direct activation of cytosolic STAT (
6、Signal transducer and activator of transcription) transcription factors.,B. PI3 kinase pathway,C. MAP kinase pathway,D. IP3/DAG pathway.,Basic function: Proliferation, differentiation and maturation of blood cells and immune cells.,Erythropoietin and red blood cells,Epo interaction withprecursor ste
7、m cells,Cloning of erythropoietin major success of biotechnology,M. Socolovsky et al., Blood 98: 3261,Janus, Roman two faced God of Gate,Janus Kinase: A tyrosine kinase tightly bound to cytosolic domain of Epo receptor,Janus Kinase/STAT signaling pathway,STAT (Signal transducer and activator of tran
8、scription),Lodish et al., ed, Molecular Cell Biology 5th, 2004.,The JAK - STAT signaling pathway,Activated by erythropoietin,STAT transcription factor,The SH2 domain of STAT bindsto phosphorylated tyrosine,Phosphorylated STATs dimerizemove to nucleus,Binding to interferon stimulated response element
9、 (ISRE) or interferon activated sequence(GAS).,Lodish et al., ed, Molecular Cell Biology 5th, 2004.,Erythropoietin (a cytokine) may activate several pathways,EPO,EpoR,JAK2,?,Expression of erythrocytes in mutant mice,Targeted disruption of Epo receptor or JAK2,These mice are wild type for JAK2 +/+,Th
10、ese mice are wild type for EpoR +/+,Note: JAK2 is downstream of EpoR,Wu et al., 1995 Cell 85:59,Neubauer et al., 1998 Cell 93:307,“. the one thing that I think is extremely important, is that anyone can do it, if given a chance, if given the opportunity.“,Telephone interview with Mario R. Capecchi i
11、mmediately following the announcement of the 2007 Nobel Prize in Physiology or Medicine, 8 October 2007. The interviewer is Adam Smith, Editor-in-Chief of Nobelprize.org.,Kirk R. Thomas and Mario R. Capecchi Site-directed mutagenesis by gene targeting in mouse embryo-derived stem cells Cell 1987, 51
12、: 503-512.,From http:/www.Nobelprize.org.,Question,STAT is a big family. Could you design an approach to identify which STAT is essential for the maturation of red blood cells?,3. Signaling through Enzyme-linked receptors,3.2 Cytokine receptors pathway,3.1 Receptor tyrosine kinase pathway,3.3 TGF re
13、ceptors pathway,3.3 TGF receptors pathway,Ligands: Transforming growth factor superfamily (TGF), bone morphogenetic protein, activin, inhibins, Nodal (mammals) and Dpp (Drosophila), etc.,Receptors: Intrinsic serine/threonine kinase protein activity in cytosolic doman (type I and II), Type III is gly
14、can without kinase activity.,Signal transduction: Direct activation of cytosolic Smad (mammalian homologues of C. elegan Sma and Drosophila Mad ) transcription factors.,Basic function: Negative regulation of cell proliferation, loss of TGF signaling contributes abnormal cell proliferation and malign
15、ancy.,Smads family,R-Smads (receptor regulated Smads): Smad2 and Smad3, etc.Co-Smads (common Samds): Smad4I-Smads (Inhibitory Smads): Smad6 and Smad7.,TGF binds type III / type II receptor,Type II (kinase) dimerizes with type I and phosphorylates it,Phosphorylation of type I results in activation of
16、 kinase activity,Phosphorylation of Smad leads to dimerization and translocation to the nucleus,TGF binding involves serine phosphorylation,Lodish et al., ed, Molecular Cell Biology 5th, 2004.,TGF signaling pathway,TFE3: Transcription factor E3Ran: small G protein,Smads complex induces expression of plasminogen activator inhibitor (PAI),Lodish et al., ed, Molecular Cell Biology 5th, 2004.,TGF pathway in physiology and pathology,Hum Mol Genet. 16 Spec No 1:R14-20. (2007),
