信号转导及其异常

Aberrant Cell Signaling and the Related DisordersDisorders of signal transduction systemsCauses Gene mutation- Function loss or gainChange of quantity of signal proteinsChange of activity of signal proteins Autoimmune diseases Secondary changesAbnormality: Ligands, Receptors, Post-receptor pathways, EffectorsDown-regulation / interruption of signalingp Signal Insufficiencyp Receptors down-regulation/desensitization: decreased quantity, binding affinity, inhibitory Ab, cofactor disorders, function loss, etc.p Defects in Adaptors, Signal transducers, Effectors (Enzymes, Transcription factors, etc)Up-regulation / over-activation of signalingp Signal Excessp Receptor up-regulation, hypersensitivity, stimulatory Ab, etcp Signal transducers, TFs: over-expression, persistent activationp OthersPathogenesis and diseases1. Aberrant SignalViral infections or other damages to pancreatic -cellinsulin productionhyperglycemiaDiabetes (Type I)(1) Aberrant Signal (Signal Insufficiency)l Insulin receptor (IR): heterotetramer (2, 2)l Insulin binding leads to change in conformationl Activates IR -subunit PTK activity l -subunit phosphorylates Tyr residues on cytoplasmic domainsas well as downstream substrates (IRS)ischemia, epilepsy, neurodegenerative diseasesextracellular glutamate/aspartic acid NMDAR activation(N-methyl-D-aspartate receptor, Ion Channel Linked Receptor)Ca2+ influx Ca2+i , activation of enzymesexcitatory intoxication(2) Aberrant Signal (Signal Excess)2. Aberrant Receptor in Cell SignalingDisturbance of receptors can occur in:u gene level, u processes of protein synthesis, post-translational modification, conformation, oligomerization, translocation, endocytosis, and etc.Receptor alterations in number, structure, function, and regulation:l down-regulation: decrease in number of receptorsl desensitization: decreased response to ligand stimulationl up regulation: increase in number of receptorsl hypersensitivity: increased response to ligand stimulation, or self-activation without ligandsReceptor diseases: receptor alterations - changes of ligand-receptor signaling - abnormal cellular effects - diseases（ 1） Receptor Gene Mutation Genetic insulin-resistant diabetes IR gene mutationsDisturbances in synthesistransfer to the membrane affinity to insulinPTK activityproteolysisType II DiabetesInsulin + IRActivate RPTK IRS PI3K Ras/Raf/MEK/ERKGlycogenSynthesis, CellTransport proliferation- The level of NO is positively correlated with ischemic injury; - Stimulation of NF-B is seen in various inflammatory responses4. Aberrant intracellular SignalingPro-carcinogen of phorbolester （ diglyceride (DG) analogy）PKC persistent activationGrowth factors Cancer gene expressionNa+/H+ exchange Intracellular pH/ K+Cell proliferation(Cancer)Aberrant intracellular Signaling佛波酯型促癌物5. Multiple Abnormalities in Signaling PathwayCancer, a set of diseases characterized by uncontrolledor inappropriate cell growth, is strongly associated with defects in signal-transduction proteins. n Ligands (GFs): e.g. EGFn Receptors (overexpression, activation of TPK): e.g. EGFRn Intracellular signal transducers：Ras gene mutation Ras-GTPase Ras activation Raf MEK ERK Proliferation TUMORMultifactor Aberrancies and Cancer-Enhancement of proliferating signalsMultifactor Aberrancies and Cancer-Deficits in proliferation-inhibiting signalTGF- + TGF-RPSTK activationSmad-phosphorylationP21/P27/P15 expressionCdk4 inhibitionCell cycle arrests at G1 phaseInhibits cell proliferation (pro-apoptosis)Lymphoma, liver cancer,Stomach cancerGene mutationNegative regulation6. Same Stimulant Induces Different Responses(the same stimuli can act on different receptors)7. Different Signals Induces the Same Pathologic Response(different receptors use the same pathway or by cross-talk)Different receptors use same pathwaysGPCR, RTK, Cytokines RsPLC Ras PI-3KPKC Raf PKBMEKERKCross talkhow hypertension leads to myocardial hypertrophy?NE, AT-IIPLCCa2+/PKCMechanic stimuliNa+, Ca2+ influxNa+-H+ exchangeMAPKTranscription factors, target genesTarget proteinsMyocardial Hypertrophy GF TGF-TPK PSTKRafRas Smad-PAlkalization8. Principles for Treatment of Aberrant Signaling-related Diseases Stratagy: To regulate the level of extracellular molecules To regulate the structure and the function of receptors To regulate the level and modifications of intracellular messengers, signal transducers, transcri