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Aberrant Cell Signaling and Related Disorders Jimin Shao (邵吉民) E-mail: [email protected] Cell signaling and signal transduction Disorders of signal transduction and mechanisms of diseases Research Progress in Signal Transduction and Diseases Cell signaling and Signal transduction --- Concept, Pathways, Function, Regulation, and networks (1) Direct Intercellular Communication Gap Junction Intercellular Communication (2) Signaling by plasma-membrane bound molecules (3) Receptor-Mediated Intercellular communication Gap Junction Receptor-Mediated Signal Transduction Systems Receptors: Cell Surface Receptors: - Ion Channel Linked Receptors - G-protein Coupled Receptors (GPCR) - Enzyme Linked Receptors Receptor tyrosine kinases Tyrosine-kinase-associated receptors Receptor serine/threonine kinases Receptor guanylyl cyclases others - Others Nuclear Receptors: - Steroid Receptors - Retinoid Receptors - Orphan Receptors General process for transmembrane signal transduction • • • • Synthesis and secretion of signaling molecules Receptor binding and initiation of intracellular signaling pathway Regulation of cellular metabolism, function, gene expression, etc Down-regulation or termination of cellular responses Cell Signaling Pathways and Networks --Physiological functions --Metabolism --Cell cycle, growth, differentiation, and apoptosis --Responses to stress --etc. LPS TNF IL-1 Disorders of signal transduction systems and Mechanisms of Diseases Causes: • Gene mutation-- Function loss or gain Change of quantity of signal proteins Change of activity of signal proteins • Epigenetic changes • Autoimmune diseases • Secondary changes Pathogenesis: Abnormality: Ligands, Receptors, Post-receptor pathways, Effectors Down-regulation / interruption of signaling Signal Insufficiency Receptors down-regulation / desensitization: decreased quantity, binding affinity, inhibitory Ab, cofactor disorders, function loss, etc. Defects in Adaptors, Signal transducers, Effectors (Enzymes, Transcription factors, etc) Up-regulation / over-activation of signaling Signal Excess Receptor up-regulation, hypersensitivity, stimulatory Ab, etc Signal transducers, TFs: over-expression, persistent activation Others 1. Aberrant Signal (1) Aberrant Signal (Signal Insufficiency) Insulin receptor (IR): heterotetramer (2, 2) Insulin binding leads to change in conformation Activates IR -subunit PTK activity -subunit phosphorylates Tyr residues on cytoplasmic domains as well as downstream substrates (IRS) Viral infections or other damages to pancreatic -cell insulin production hyperglycemia Diabetes (Type I) (2) Aberrant Signal (Signal Excess) ischemia, epilepsy, neurodegenerative diseases extracellular glutamate/aspartic acid NMDAR activation (N-methyl-D-aspartate receptor, Ion Channel Linked Receptor) Ca2+ influx [Ca2+]i , activation of enzymes excitatory intoxication 2. Aberrant Receptor in Cell Signaling Disturbance of receptors can occur in: gene level, processes of protein synthesis, post-translational modification, conformation, oligomerization, translocation, endocytosis, degradaion, etc. Receptor alterations in number, structure, function, and regulation can result in: down-regulation: decrease in number of receptors desensitization: decreased response to ligand stimulation up regulation: increase in number of receptors hypersensitivity: increased response to ligand stimulation, or self-activation without ligands Receptor diseases: receptor alterations --- changes of ligand-receptor signaling --abnormal cellular effects --- diseases （1）Receptor Gene Mutation Insulin + IR Genetic insulin-resistant diabetes: IR gene mutations Activate RPTK IRS PI3K Ras/Raf/ MEK/ERK Glycogen Synthesis, Cell Transport proliferation & Utilization Disturbances in synthesis transfer to the membrane affinity to insulin PTK activity proteolysis Type II Diabetes (2) Autoimmune diseases-thyropathy Stimulatory Ab Blocking Ab TSH-R（GPCR) 30~35 residues Gs TSH-R Gq AC 295~302 385~395 residues PLC cAMP IP3 Ca2+ DAG Binding of TSH to R↓ PKC Thyroid proliferation & secretion of thyroxine hypothyroidism hyperthyroidism Graves病（弥漫性毒性甲状腺肿） 刺激性抗体模拟TSH 的作用 促进甲状腺素分泌和甲状腺腺体生长 女性>男性 甲亢、甲状腺弥漫性肿大、突眼 桥本病 (Hashimoto’s thyroditis,慢性淋巴细胞性甲状腺炎) 阻断性抗体与TSH受体结合 减弱或消除了TSH的作用 抑制甲状腺素分泌 甲状腺功能减退、黏液性水肿 (3)Secondary Abnormality in Receptors Heart failure, Myocardial hypertrophy -adrenergic receptors (GPCR) down regulated or desensitized Reaction to catecholamines Myocardial contraction Alleviate myocardial lesion Accelerate heart failure 受体异常疾病 分类 累及的受体 主要临床特征 家族性高胆固醇血症 LDL受体 血浆LDL升高，脂质代谢紊乱，动脉粥样硬化 家族性肾性尿崩症 ADH V2型受体(GPCR) 男性发病，多尿、口渴和多饮 视紫质 进行性视力减退 视锥细胞视蛋白 色觉异常 IL-2受体γ链 T细胞减少或缺失，反复感染 Cccccccccccccccc II型糖尿病 胰岛素受体(RTK) 高血糖,血浆胰岛素正常或升高 ccc核受体异常 ccc雄激素抵抗综合征 雄激素受体 不育症，睾丸女性化 cccccccccccccccc维生素D抵抗性佝偻病 维生素D受体 佝偻病骨损害，秃发，继发性甲状旁腺素增高 Cccccccccccccccc甲状腺素抵抗综合征 β甲状腺素受体 甲状腺功能减退，生长迟缓 cccccccccccccccc雌激素抵抗综合征 雌激素受体 骨质疏松，不孕症 Ccccccccccccccc 糖皮质激素抵抗综合征 糖皮质激素受体 多毛症,性早熟,低肾素性高血压 遗传性受体病 膜受体异常 c视网膜色素变性 Cccccccccccccccc 遗传性色盲 11111111111111 严重联合免疫缺陷症 自身免疫性受体病 cccccccccccccccc重症肌无力 nAch受体 活动后肌无力 cccccccccccccccc自身免疫性甲状腺病 刺激性TSH受体(GPCR) 抑制性TSH受体 甲亢和甲状腺肿大 甲状腺功能减退 ccccccccccccccccII型糖尿病 胰岛素受体 高血糖，血浆胰岛素正常或升高 cccccccccccccccc艾迪生病 ACTH受体 色素沉着，乏力，血压低 继发性受体异常 ccccccccccccccc心力衰竭 肾上腺素能受体 心肌收缩力降低 ccccccccccccccc帕金森病 多巴胺受体 肌张力增高或强直僵硬 ccccccccccccccc肥胖 胰岛素受体 血糖升高 ccccccccccccccc肿瘤 生长因子受体 细胞过度增殖 3. Aberrant G-protein in Cell Signaling (1) G-protein gene mutation Pituitary tumor: Gs gene mutation At Arg201 or Gln227 Hypothalamus GHRH Pituitary gland GHRH-R Gs GTPase activity Persistent activation of Gs Persistent activation of AC cAMP Ac Pituitary proliferation and secretion cAMP GH Acromegaly in adults Gigantism in children (2) G-protein modification Cholera toxin intestinal epithelia Gs ribosylation at Arg201 Inactivation of GTPase Persistent activation of Gs and Ac, cAMP secretion of chloride into the lumen, inhibition of sodium uptake from the lumen, Large volumes of fluid into the lumen of the gut Diarrhea and dehydration Circulation failure 4. Aberrant intracellular Signaling • The intracellular signaling involves various messengers, transducers, and transcription factors. • Disorders can occur in any of these settings, e.g.: -- Calcium overload is a general pathological process in various diseases; -- The level of NO is positively correlated with ischemic injury; -- Stimulation of NF-B is seen in various inflammatory responses --Aberrant intracellular Signaling in carcinogenesis Pro-carcinogen of phorbol ester （diglyceride (DG) analogy） PKC persistent activation Growth factors Cancer gene expression Na+/H+ exchange Intracellular pH↑/ K+↑ Cell proliferation (Cancer) 5. Multiple Abnormalities in Signaling Pathways Major signaling pathways relevant to cancer Multifactor Aberrancies in Cancer ---Enhancement of proliferating signals Ligands (GFs): e.g. EGF Receptors (overexpression, activation of TPK): e.g. EGFR Intracellular signal transducers： Ras gene mutation Ras-GTPase Ras activation Raf MEK ERK Proliferation TUMOR ---Deficits in proliferation-inhibiting signals TGF- + TGF-R PSTK activation Smad-phosphorylation Gene mutation Negative regulation P21/P27/P15 expression Cdk4 inhibition Cell cycle arrests at G1 phase Inhibits cell proliferation (pro-apoptosis) Lymphoma, liver cancer, Stomach cancer Jason I. Herschkowitz and Xiaoyong Fu. MicroRNAs Add an Additional Layer to the Complexity of Cell Signaling. Sci. Signal.4 (184), jc5. [DOI: 10.1126/scisignal.2002182] 6. Relationship between Stimulants and Pathological Effects --Same Stimulant Induces Different Responses (the same stimuli can act on different receptors) --Different Signals Induces the Same Pathologic Response (different receptors use the same pathway or by cross-talk) --Different receptors use same pathways GPCR, RTK, Cytokines Rs PLC PKC Ras PI-3K Raf PKB MEK ERK --Cross talk: hypertension leads to myocardial hypertrophy Mechanic stimuli Na+, Ca2+ influx Na+-H+ exchange Alkalization NE, AT-II GF TGF- PLC TPK PSTK Ca2+/PKC Ras Smad-P Raf MAPK Transcription factors, target genes Target proteins Myocardial Hypertrophy 7. 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 modification enzymes, messengers, signal transducers, transcription factors, effectors, etc Target therapy: • • Breast cancer: EGFR overexpression –Herceptin (mAB) Chronic myeloid leukemia (CML): Bcr-Abl (abnormal tyrosine kinase) — Gleevec (small compound inhibitor) Research Progress in Signal Transduction and Diseases
