Aberrant Cell Signaling and Related Disorders

Jimin Shao ( 邵吉民 )

E-mail: shaojimin@zju.edu.cn

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

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

Receptor-Mediated Signal Transduction Systems

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.

LPSTNFIL-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

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

Pathogenesis:

Abnormality: Ligands, Receptors, Post-receptor pathways, Effectors

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 -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+]i , activation of enzymes

excitatory intoxication

(2) Aberrant Signal (Signal Excess)

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

Genetic insulin-resistant diabetes: IR gene mutations

Disturbances in synthesis transfer to the membrane affinity to insulin PTK activity proteolysis

Type II Diabetes

Insulin + IR

Activate RPTK

IRS

PI3K Ras/Raf/ MEK/ERKGlycogenSynthesis, CellTransport proliferation& Utilization

Binding of TSH to R↓

hypothyroidism

(2) Autoimmune diseases-thyropathy

Blocking Ab

TSH-R295~302385~395 residues

Gs

AC

cAMP

Thyroid proliferation & secretion of thyroxine

Gq

PLC

IP3DAG

Ca2+ PKC

TSH-R （ GPCR)30~35

residues

Stimulatory Ab

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 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 tumor: Gs gene mutationAt Arg201 or Gln227

GTPase activity

Persistent activation of Gs

Persistent activation of AC

cAMP

Pituitary proliferation and secretion

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 volumes of fluid into the lumen of the gut

Diarrhea and dehydrationCirculation failure

• 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

4. Aberrant intracellular Signaling

Pro-carcinogen of phorbol ester （ diglyceride (DG) analogy ）

PKC persistent activation

Growth factors

Cancer gene expressionNa+/H+ exchange

Intracellular pH↑/ K+↑

Cell proliferation

(Cancer)

--Aberrant intracellular Signaling in carcinogenesis

5. Multiple Abnormalities in Signaling Pathways

Major signaling pathways relevant to cancer

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

Multifactor Aberrancies in Cancer

---Enhancement of proliferating signals

---Deficits in proliferation-inhibiting signals

TGF- + TGF-R

PSTK activation

Smad-phosphorylation

P21/P27/P15 expression

Cdk4 inhibition

Cell cycle arrests at G1 phase

Inhibits cell proliferation (pro-apoptosis)

Lymphoma, liver cancer,

Stomach cancer

Gene mutation

Negative regulation

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 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

--Cross talk: 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,

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