Aberrant Cell Signaling and the Related Disorders
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Transcript of Aberrant Cell Signaling and the Related Disorders
Aberrant Cell Signaling and the Related Disorders
Jimin Shao ( 邵吉民 )Professor, Dept. Pathology and PathophysiologyTel: 88208209E-mail: [email protected]
(1) Causes• Gene mutation-- Function loss or gain
Quantity change of signaling pathway proteins Activity change of signaling pathway proteins
• Autoimmune diseases• Secondary changes
(2) PathogenesisAbnormality: Ligands, Receptors, Post-receptor components, 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, TFs, other Effectors, etc.Up-regulation / over-activation of signaling• Signal Excess• Receptor up-regulation, hypersensitivity, stimulatory Ab, etc• Signal transducers, TFs: over-expression, persistent activation, etc.
1. Aberrant Signal
Viral infections or other damages to pancreatic -cell
insulin production
hyperglycemia
Diabetes (Type I)
(1) Aberrant Signal (Signal Insufficiency) Insulin receptor (IR): heterotetramer (2, 2) Insulin binding leads to change in conformation Activates IR -subunit (PTK activity) IR-subunit phosphorylates Tyr residues on cytoplasmic domains as well as downstream substrates (IRS)
ischemia, epilepsy, neurodegenerative diseases
extracellular glutamate/aspartic acid
NMDAR activation(N-methyl-D-aspartate receptor, Ion Channel Linked Receptor)
Ca2+ influx
[Ca2+] , activation of enzymes
excitatory intoxication
(2) Aberrant Signal (Signal Excess)
Disturbance of receptors can occur in: gene level, Protein level: synthesis, post-translational modification, conformation,
oligomerization, translocation, endocytosis, degradation, and etc.
Receptor alterations in number, structure, function, and regulation lead to:
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
2. Aberrant Receptor in Cell Signaling
( 1 ) Receptor Gene Mutation
Genetic insulin-resistant diabetes IR gene mutations
Disturbances in synthesis transfer to the membrane affinity to insulin PTK activity proteolysis/degradation
Type II Diabetes
Insulin
Activate IR(RPTK)
IRS
PI3K Ras/Raf/MEK/ERK
Glu Transport & Utilization,Glycogen Synthesis, etcCell proliferation
(2) Autoimmune diseases-thyropathy
Gs
AC
cAMP
Thyroid proliferation & secretion of thyroxine
Gq
PLC
IP3DAG
Ca2+ PKC
TSH-R ( GPCR)30~35
residues
Stimulatory Ab
hyperthyroidism
Binding of TSH to R
hypothyroidism
Blocking Ab
TSH-R(295~302385~395
residues )
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 Accelerate myocardial lesion heart failure
分类 累及的受体 主要临床特征
遗传性受体病 膜受体异常 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
c 视网膜色素变性 视紫质 进行性视力减退
Cccccccccccccccc 遗传性色盲 视锥细胞视蛋白 色觉异常
11111111111111 严重联合免疫缺陷症
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
受体异常疾病
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-proteinin Cell Signaling
Pituitary proliferation and secretion
Pituitary tumor: Gs gene mutation At Arg201 or Gln227
GTPase activity
Persistent activation of Gs
Persistent activation of AC
cAMP
Acromegaly in adults Gigantism in children
(1) G-protein gene mutation
HypothalamusGHRH
Pituitary glandGHRH-R
Gs
Ac
cAMP GH
(2) G-protein modification
Cholera toxinintestinal epithelia
Gs ribosylation at Arg201Inactivation of GTPase
Persistent activation of Gs and Ac, cAMP
secretion of chloride into the lumen,inhibition of sodium uptake from the lumen,
Large volumns of fluid into the lumen of the gut
Diarrhea and dehydrationCirculation failure
• The intracellular signaling involves
-- various messengers, transducers, transcription factors, and others.
• Disorders can occur in any of these settings, e.g.-- Stimulation of NF-B is seen in various inflammatory responses
-- Calcium overload is a general pathological process in various diseases;
-- The level of NO is positively correlated with ischemic injury;
4. Aberrant intracellular Signaling
Ligands (GFs): e.g. EGF
Receptors (overexpression, activation of PTK): e.g. EGFR
Intracellular signal transducers : Ras gene mutation Ras-GTPase Ras activation
Raf MEK ERK
Proliferation TUMOR
---Enhancement of multiple proliferating signals in Cancer
5. Multiple Abnormalities in Signaling Pathway
6. Relationship between Stimulants and Pathological Effects
(1) Same Stimulant Induces Different Responses(the same stimuli can act on different receptors)
(2) Different Signals Induces the Same Pathologic Response(different receptors use the same pathway or by cross-talk)
(3) Different receptors use same pathways
GPCR, RTK, Cytokines Rs
PLC Ras PI-3K
PKC Raf PKB
MEK
ERK
NE, AT-II
PLC
Ca2+/PKC
Mechanic stimuli
Na+, Ca2+ influx
Na+-H+ exchange
MAPK
Transcription factors, target genesTarget proteins
Myocardial Hypertrophy
GF TGF-
TPK PSTK
Raf
Ras Smad-PAlkalization
(4) Cross talk—how hypertension leads to 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,
intracellular messengers, signal transducers, transcription factors, etc
Target therapy: • Breast cancer: EGFR overexpression –Herceptin (mAB)• Chronic myeloid leukemia (CML): Bcr-Abl (abnormal tyrosine kinase) — Gleevec (small compound
inhibitor)