Transcript 邵吉民_Signaling_and_diseases

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
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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)
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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:
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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:
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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）
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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)
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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:
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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:
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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