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Signal Transduction and the Related Disorders. Basic Concept of Cell Signaling (trans-membranous signaling). The process in which cells

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Basic Concept of Cell Signaling

(trans-membranous signaling)

The process in which cells

sensethe extracellular stimuli through membranous or intracellular receptors, transducethe signals via intracellular molecules, and thus regulatethe biological function of the cells


Major pathways for cell signaling

G-protein-mediated pathway

Adenylate cyclase mediated pathway

Phospholipase mediated pathway

Small G-protein-mediated pathway

Non-G-protein-mediated pathway

Receptor tyrosine kinase mediated pathway

Receptor serine/threonine kinase mediated pathway

Receptor guanilate cyclase mediated pathway

Intracellular (unclear) receptor mediated pathway



General process for

transmembrane signal transduction



Types of cellular signals

  • Physical signals

  • Light, electronic, mechanic, UV, heat, volume or osmotic, etc

  • Chemical signals

  • Hormones, neurotransmitters, GFs, cytokines; odor molecules; ATP, active oxygen; drugs, toxins, etc


Modes for the function of endogenous signals

Endocrine Act on a far away organ via blood

circulation, seen in most hormones

Paracrine Act on a nearby target, seen in GFs, PG, NO

Autocrine Act on itself after secreted, seen in GFs,

especially in tumor tissues

Intricrine Act on itself before secreted, seen

in nuclear receptors

Synaptic:Presynaptic to postsynaptic,

seen in neurotransmitters


Aberrant Signal (Signal Excess)

ischemia, epilepsy, neurodegenerative diseases

extracellular glutamate/aspartic acid

NMDAR activation

Ca2+ influx

[Ca2+]i , activation of enzymes

excitatory intoxication


Aberrant Signal (Signal Insufficiency)

Lesions in pancreatic -cell

Decreased insulin production

hyperglycemia

Diabetes (Type I)


Aberrant Signal(autoimmune-thyropathy)

Stimulatory Ab

TSH-R

30~35aa

residues

Gs

Gq

AC

PLC

cAMP

DG

IP3

PKC

Ca2+

Thyroid proliferation & secretion

hyperthyroidism

Blocking Ab

TSH-R

295~302

385~395

AA residues

Binding of TSH to R↓

hypothyroidism


2. Aberrant Receptor in Cell Signaling

  • Receptor gene mutation

  • Receptor down regulation or

  • desensitization


Receptor gene mutation genetic insulin resistant diabetes
Receptor Gene Mutation — Genetic insulin-resistant diabetes

Insulin+R

Activate RPTK

IRS

PI3K Ras/Raf/

MEK/ERK

Glycogen

Synthesis, Cell

Transport proliferation

& Utilization

IR gene mutations

Disturbances in synthesis

in transfer to the membrane

in affinity to insulin

in RPTK activation

in proteolysis

Type II Diabetes


Response of the insulin receptor kinase irk to ligand binding
Response of the insulin receptor kinase (IRK) to ligand binding

  • Heterotetramer (2, 2)

  • Insulin binding leads to change in structure

  • Conformation change activates -subunit TK activity

  • -subunit phosphorylates Tyr residues on cytoplasmic domains as well as downstream substrates (IRS)


Three dimensional structures of the insulin receptor tyrosine kinase irk
Three-dimensional structures of the insulin receptor tyrosine kinase (IRK)

IRK conformational change upon activation loop phosphorylation. The N-terminal lobe of IRK is colored white and the C-terminal lobe is colored dark grey. The activation loop (green) contains autophosphorylation sites Y1158, Y1162 and Y1163, and the catalytic loop (orange) contains the putative catalytic base, D1132. Also shown are the unbound/bound ATP analog and tyrosine-containing substrate peptide (pink). [Hubbard, EMBO J. 16, 5572 (1997)]


Once tyr phosphorylated the irk activity trigerrs a number of signaling pathways
Once Tyr-Phosphorylated, the IRK activity trigerrs a number of signaling pathways

  • Phosphatidylinositol 3-hydroxy kinase, makes PIP2,PIP3

  • Grb2, Sos, activates Ras

  • Activation of PLC


Receptor tyrosine kinases
Receptor Tyrosine Kinases of signaling pathways


Receptor Gene Mutation of signaling pathways(NDI)

ADH + ADHV2-R

Gene mutation

Gs

V2R synthase↓

or affinity↓

cAMP

ADH reaction in collecting tubules↓

AQP2 moves to lumen side in collecting tubules

Diuresis

Permeability↑

Nephrogenic Ddiabetes

Insipidus

H2O absorption 


Secondary Abnormality in Receptors of signaling pathways

(Heart failure)

  • Myocardial hypertrophy

  • -R1 down regulated or desensitized

    Reaction to catecholamine

    Myocardial contraction

    Alleviate Accelerate

    myocardial lesion heart failure


3. Aberrant G-protein of signaling pathways

in Cell Signaling


G-protein-Mediated Pathway of signaling pathways


Activation of Adenylate Cyclase by Gs of signaling pathways


GTPase of signaling pathways

Regulation of G-Protein Activity


G-protein gene mutation of signaling pathways—pituitarytumor

Gs gene mutation

GHRH

Pituitary

Gs

GH

GTPase activity

Persistent activation of Gs

Persistent activation of AC

cAMP

Pituitary proliferation and secretion

Acromegaly or Gigantism


G-protein gene mutation— of signaling pathwaystype 1A-PHP

Type 1A PHP is a genetic disease caused by Gsgene mutation

type 1A Gs gene mutation expression of Gs disconnection between PTH receptor and AC hyperphosphatemia

type 1B the target organ resists to PTH,

the Gs is normal


G-protein modification of signaling pathways——cholera

Cholera toxin

Gsribosylation at Arg201

Inactivation of GTPase

Persistent activation of Gsand cAMP

Conformational alteration of intestinal epithelia

Cl- and H2O to lumen of intestine

Diarrhea and dehydration

Circulation failure



Aberrant intracellular Signaling of signaling pathways

Pro-carcinogen of phorbolester

PKC persistent activation

Growth factors

Cancer gene expression

Na+/H+ exchange 

Intracellular pH↑/ K+↑

Cell proliferation

(Cancer)


Aberrant intracellular Signaling of signaling pathways

The intracellular signaling involves various messengers, transducers and transcription factors. Disorders can occur in any of these settings.

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


5. of signaling pathwaysMultiple Abnormalities in Signaling Pathway


The sympathetic regulation in heart failure of signaling pathways

Normal

Hypertrophy, heart failure

CA

Density of SN↓;tyrosine hydroxylase↓

β-R down regulated;

pH↓→ reaction of R to CA↓

1R

Gs

Gs↓,function↓;Gi, function 

cAMP


cAMP of signaling pathways

Ca2+channel

SR phospholamban

Ca2+ influx

Ca2+ pump

SR pump↓

SR Ca2+channel

[Ca2+] i ↓

Myocardial dilation

[Ca2+] i

Myocardial contraction

H+ inhibits binding of Ca2+ to troponin


Multifactor Aberrancies and Cancer of signaling pathways

(Enhancement of proliferating signals)

  • Ligands (GFs)

  • Receptors (overexpression, activation of TPK)

  • Intracellular transducers:

    Ras mutation Ras-GTPase Ras activation

    Raf MEK ERK Proliferation TUMOR


Multifactor Aberrancies and Cancer of signaling pathways

(Deficits in proliferation-inhibiting signal)

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


6. Same Stimulant Induces Different Responses of signaling pathways

(the same stimuli can act on different receptors)


Infectious Shock of signaling pathways

-R

β-R

KCa2+

Excitatory sympathetic nerve stimuli

IP3/DG pathway

Gs

Gq

AC pathway

PLC

AC

cAMP

IP3

DG

PKA

PKC

Ca2+

Ca2+pump

MLCK

CaMK

Myosin

[Ca2+]i

Artery Contraction

A-V shunt


7. Different Signals Induces the Same Pathologic Response of signaling pathways

(different receptors use the same pathway or by cross-talk)


Different receptors use same pathways of signaling pathways

GPCR, RTKR, Cytokines Rs

PLC Ras PI-3K

PKC Raf PKB

MEK

ERK


Cross talk—how hypertension of signaling pathways

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

Myocardial Hypertrophy



Principles for Treatment Diseases

  • To regulate the level of extracellular molecules

  • To regulate the structure and the function of receptors

  • To regulate the level and modifications of intracellular messenger molecules and transducers

  • To regulate the level of nuclear transcription factors


LPS Diseases

TNF

IL-1


Regulating of signal transduction Diseases

in treatment of diseases



Regulating Signal Transduction in Research Research

P

P

P

P

P

P

Normal tau

Normal tau

P

P

P

P

P

P

P

P

P

P

P

P

P

P

P

P

P

P

P

AD p- tau

S9/21

S9/21

S9/21

S473

T308

Active

GSK-3/

Inactive

GSK-3/

Active

GSK-3/

Inactive

PKB

PDK1/PDK2

PI3-K

GF-109203X

PKC

AD p- tau

Caspase-3

P

P

P

WT


Mutation Research

TSH + R

Gs Gq Ras

AC PLC Raf

cAMP DAG ERK

PKA PKC

Thyroxine Secretion

Thyroid Gland Growth

Loss of function

Hypothyroidism

Gain of function

Hyperthyroidism

Gain or loss of function mutations?


Dominant negative effect? Research

Mutation causes not only self-dysfunction

but also inactivates or inhibits wild type counterparts

The mutation is called dominant negative mutant

For example, mutated nuclear receptor competes with

wild type receptors to bind to the target gene

and thus inhibits the transcription activity of wild type genes


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