Aberrant Cell Signaling and  Related Disorders
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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.

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Aberrant Cell Signaling and Related Disorders

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Aberrant cell signaling and related disorders

Aberrant Cell Signaling and Related Disorders

Jimin Shao (邵吉民)

E-mail: [email protected]


Aberrant cell signaling and related disorders

Cell signaling and signal transductionDisorders of signal transduction and mechanisms of diseasesResearch Progress in Signal Transduction and Diseases


Cell signaling and signal transduction concept pathways function regulation and networks

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


Aberrant cell signaling and related disorders

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


Aberrant cell signaling and related disorders

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


Aberrant cell signaling and related disorders

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

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


Aberrant cell signaling and related disorders

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


Aberrant cell signaling and related disorders

1. Aberrant Signal


Aberrant cell signaling and related disorders

(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)


Aberrant cell signaling and related disorders

(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


Aberrant cell signaling and related disorders

2. Aberrant Receptor

in Cell Signaling


Aberrant cell signaling and related disorders

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

(1)Receptor Gene Mutation

Insulin + IR

Activate RPTK

IRS

PI3K Ras/Raf/

MEK/ERK

Glycogen

Synthesis, Cell

Transport proliferation

& Utilization

Genetic insulin-resistant diabetes:

IR gene mutations

Disturbances in

synthesis

transfer to the membrane

affinity to insulin

PTK activity

proteolysis

Type II Diabetes


Aberrant cell signaling and related disorders

Stimulatory Ab

TSH-R(GPCR)

30~35

residues

Gs

Gq

AC

PLC

cAMP

DAG

IP3

PKC

Ca2+

Thyroid proliferation & secretion of thyroxine 

hyperthyroidism

(2) Autoimmune diseases-thyropathy

Blocking Ab

TSH-R

295~302

385~395

residues

Binding of TSH to R↓

hypothyroidism


Aberrant cell signaling and related disorders

  • 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


Aberrant cell signaling and related disorders

  • Heart failure, Myocardial hypertrophy

  • -adrenergic receptors (GPCR)

    down regulated or desensitized

    Reaction to catecholamines

    Myocardial contraction

    Alleviate Accelerate

    myocardial lesion heart failure

(3)Secondary Abnormality in Receptors


Aberrant cell signaling and related disorders

受体异常疾病


Aberrant cell signaling and related disorders

3. Aberrant G-protein

in Cell Signaling


Aberrant cell signaling and related disorders

Pituitarytumor:Gs gene mutation

At Arg201 or Gln227

Hypothalamus

GHRH

Pituitary gland

GHRH-R

Gs

Ac

cAMP

GH

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


Aberrant cell signaling and related disorders

(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


Aberrant cell signaling and related disorders

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 cell signaling and related disorders

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)

--Aberrant intracellular Signaling in carcinogenesis


Aberrant cell signaling and related disorders

5.Multiple Abnormalities in Signaling Pathways


Aberrant cell signaling and related disorders

Major signaling pathways relevant to cancer


Aberrant cell signaling and related disorders

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


Aberrant cell signaling and related disorders

TGF- + TGF-R

PSTK activation

Smad-phosphorylation

P21/P27/P15 expression

Cdk4 inhibition

Cell cycle arrests at G1 phase

Inhibits cell proliferation

(pro-apoptosis)

Gene mutation

Negative regulation

Lymphoma,

liver cancer,

Stomach cancer

---Deficits in proliferation-inhibiting signals


Aberrant cell signaling and related disorders

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]


Aberrant cell signaling and related disorders

  • 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)


Aberrant cell signaling and related disorders

--Different receptors use same pathways

GPCR, RTK, Cytokines Rs

PLC Ras PI-3K

PKC Raf PKB

MEK

ERK


Aberrant cell signaling and related disorders

--Cross talk: hypertension leads to myocardial hypertrophy

Mechanic stimuli

GF TGF-

NE, AT-II

Na+, Ca2+ influx

Na+-H+ exchange

PLC

TPK PSTK

Ca2+/PKC

Ras Smad-P

Alkalization

Raf

MAPK

Transcription factors, target genes

Target proteins

Myocardial Hypertrophy


Aberrant cell signaling and related disorders

  • 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)

7. Principles for Treatment of

Aberrant Signaling-related Diseases


Aberrant cell signaling and related disorders

Research Progress in Signal Transduction and Diseases


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