信號轉(zhuǎn)導(dǎo)及異常

1、Cell Signal Transduction and Diseases Jimin Shao (邵吉民), Ph.D.Professor & Director, PathophysiologyTel: 88208209E-mail: 1. Cell signaling and Signal transduction2. Gap junction and diseases3. Receptor-Mediated Signal Transduction and diseases (1) Cell-surface receptors (2) Nuclear receptors (3) D

2、isorders of signal transduction systemsCell signaling and Signal transduction1. Cell Signaling (1) Direct Intercellular Communication Gap Junction Intercellular Communication (GJTC)(2) Signaling by plasma-membrane bound molecules (3) Receptor-Mediated Intercellular communication Cell-Surface Recepto

3、rsIon channel linked receptorsG-protein coupled receptorsEnzyme linked receptors Nuclear Receptors Steroid Receptors Retinoid Receptors Orphan ReceptorsGap Junction2. Types of cellular signals(1) Physical signals Light, electronic, mechanic, UV, heat, volume or osmotic, etc (2) Chemical signals Horm

4、ones, neurotransmitters, Growth factors, cytokines; odor molecules; ATP, active oxygen; drugs, toxins, etcEndocrine Act on a far away organ via blood circulation, seen in most hormones Paracrine Act on a nearby target, seen in GFs, CKs, etc Synaptic: Presynaptic to postsynaptic (neurotransmitters) A

5、utocrine Act on itself after secreted, seen in GFs, especially in tumor tissues Intracrine Act on itself before secreted, seen in nuclear receptors3. Modes for the function of endogenous signals1. Structure of Gap JunctionlConnexins are four-pass transmembrane proteins, six of which assemble to form

6、 a channel, a connexon.l 20 different isoforms of connexins in humans and miceGap junction Used by most cells in animal tissues with the exception of a few terminally differentiated cells, such as skeletal muscle cells and blood cells Allowing inorganic ions and other small water-soluble molecules t

7、o pass directly from one cell to the other, thus coupling the cells both electrically and metabolicallyuIn electrically excitable cells such as nerve cells allow action potential to spread rapidly without the delay that occurs at chemical synapsesuThe sharing of small metabolites and ions provides a

8、 mechanism for coordinating the activities of individual cells (metabolic cooperation)2. Function of Gap Junction 3. Gap Junction in Diseases Connexin gene mutation and Diseases Congenital non-syndromatic deafness (Cx26 mutation) Congenital cataract (Cx50 mutation) Axonal degeneration of peripheral

9、nerves (Cx32 mutation) Infertility of females (Cx37) Gap junction and tumor promotion - Gap junction intercellular communication down-regulated - connexin transfection for up-regulation Gap junction and embryogenesis - embryo development (Cx43) - nutrients transportation (Cx26) Others Receptors: Cel

10、l Surface Receptors: - Ion Channel Linked Receptors - G-protein Coupled Receptors (GPCR) - Enzyme Linked Receptors - Others Nuclear Receptors: - Steroid Receptors - Retinoid Receptors - Orphan ReceptorsReceptor-Mediated Signal Transduction Systems1.Classification of cell-surface receptors Ion-channe

11、l-linked receptors Involved in rapid synaptic signaling between electrically excitable cells G-protein coupled receptors (GPCR) Seven-pass transmembrane protein, indirectly regulate the activity of a target protein through a trimeric GTP-binding protein (G-protein) Enzyme-linked receptors Single-pas

12、s transmembrane protein, function directly as enzyme or directly associated with enzymes they activate Cell-surface receptors2. General process for transmembrane signal transduction Synthesis and secretion of signaling moleculesReceptor binding and initiation of intracellular signaling pathwayRegula

13、tion of cellular metabolism, function, gene expression, etcDown-regulation or termination of cellular responsesIon Channel Linked Receptor(Synonyms: Ligand-gated Ion Chennel)1. Classification: Class I nAchR, GABAAR, 5-HT3R, GlyR Class II Glutamate/Aspartate Receptor Class III cGMP/cAMPR, IP3R, ryano

14、dine R Class IV ATP/ADP gated channel (P2X)2. Structure of Ion Channel Linked Receptors3. Involved in rapid synaptic signaling between electrically excitable cells-A model for iGluR activation and desensitization1. Diagram of GPCR Structure and Changes After its Activation GPCR: seven-pass transmemb

15、rane proteinSignaling through GPCR2. G-protein:three non-identical subunits(1) Gs, Gi: regulating the production of cAMP cAMP is synthesized from ATP by membrane-bound adenylyl cyclase, and rapidly hydrolyzed by cAMP phosphodiesterase Stimulatory G protein (Gs), activates Ac Inhibitory G protein (Gi

16、), inhibits Ac Usually the a subnit that regulates the cyclase, although bg complex may does so as well Important targets for bacterial toxins(2) Gq: activate the inositol phospholipid signaling pathway by activating phospholipase C-b b Gq activates PLC-b PLC-b acts on phosphatidylinositol 4,5-bipho

17、sphate PI(4,5)P2 to generate: inositol (1,4,5)-triphosphate (IP3) diacylglycerol (DAG)3. GPCR Signaling PathwaysRegulator of G-protein signaling DAG GPCR*GPAccAMPPKACREB(CRE-binding protein) + CBPCRE of target gene GPCR*GPPLC IP3Ca2+ CalmodulinCaM-Kinase DAG + Ca2+ PKCSignaling through enzyme-linked

18、 cell-surface receptors1. Receptor tyrosine kinases2. Tyrosine-kinase-associated receptors3. Receptor serine/threonine kinases4. Receptor guanylyl cyclases5. others1. Receptor tyrosine kinases Many secreted growth factors and hormones act through receptor tyrosine kinases: Epithelial growth factor (

19、EGF), platelet-derived growth factor (PDGF), fibroblast growth factors (FGFs), hepatocyte growth factor (HGF), insulin, insulinlike growth factor-1 (IGF-1), vascular endothelial growth factor (VEGF), macrophage-colony-stimulating factor (M-CGF), neurotrophins Many cell-surface-bound signal proteins

20、also act through receptor tyrosine kinases Ephrins (Eph): regulates cell adhesion and repulsion response that guide the migration of cells and axons during development Eph receptors: receptor tyrosine kinases Bidirectional signaling: binding to Eph receptor can cause the activation of both Eph and E

21、ph receptor, thus changing the behavior of both cellsActivated receptor tyrosine kinases phosphorylate themselves(1) RAS-MAPK PathwayGF-RTK-Grb2Ras GEFRas -MAPKKKMAPKK-MAPK (RafMEK1/2ERK1/2) (2) PI3-kinase/Protein kinase B pathwayPKB(or Akt) containing a PH domain -Binds to PI(3,4,5)P3 -Activated by

22、 a phosphatidylinositol-dependent protein kinase PDK1 -Phosphorylates and inactivates BAD, a pro-apoptosis factor, promotes cell survivalCross-talk between signaling pathways activated by GPCRs and RTKsCytokines -receptors -Jak-STAT signal pathway2. Tyrosine-kinase-associated receptors STATs also co

23、ntain SH2 domain and dock onto specific activated receptor TK, thus being activated independent of Jaks Ligands: interferons, cytokines, etc JAK family: JAK1-3, Tyk 2 (Just Another Kinase/Janus Kinase) (cytoplasmic tyrosine kinases) STAT family: STAT1-7 (Signal Transducer and Activator of Transcript

24、ion Jaks phosphorylate and activate STATs -STATs then move to the nucleus and stimulate transcription3. Receptor serine/threonine kinasesTGF-b superfamily-receptor serine/threonine kinases-Smads Signal Pathway Transforming growth factor-b superfamily: TGF-bs, activins, bond morphogenetic proteins (BMPs), etc TGF- Receptor Superfamily: Protein serine/threonine kinase; Single pass transmembrane receptor; Type I and II The ligand first binds to and activates type II homodimer, which recruits, phosphorylates, and activates a type I receptor dimer, forming a tetrameric receptor complex