Signal Transduction and the Related Disorders
This presentation is the property of its rightful owner.
Sponsored Links
1 / 47

Signal Transduction and the Related Disorders PowerPoint PPT Presentation


  • 48 Views
  • Uploaded on
  • Presentation posted in: General

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

Download Presentation

Signal Transduction and the Related Disorders

An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -

Presentation Transcript


Signal transduction and the related disorders

Signal Transduction and the Related Disorders


Signal transduction and the related disorders

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


Signal transduction and the related disorders

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


Signal transduction and the related disorders

Aberrant Cell Signaling and the Related Disorders


Signal transduction and the related disorders

General process for

transmembrane signal transduction


Signal transduction and the related disorders

1. Aberrant Signal


Signal transduction and the related disorders

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


Signal transduction and the related disorders

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


Signal transduction and the related disorders

Aberrant Signal (Signal Excess)

ischemia, epilepsy, neurodegenerative diseases

extracellular glutamate/aspartic acid

NMDAR activation

Ca2+ influx

[Ca2+]i , activation of enzymes

excitatory intoxication


Signal transduction and the related disorders

Aberrant Signal (Signal Insufficiency)

Lesions in pancreatic -cell

Decreased insulin production

hyperglycemia

Diabetes (Type I)


Signal transduction and the related disorders

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


Signal transduction and the related disorders

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


Signal transduction and the related disorders

Receptor Gene Mutation (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 


Signal transduction and the related disorders

Secondary Abnormality in Receptors

(Heart failure)

  • Myocardial hypertrophy

  • -R1 down regulated or desensitized

    Reaction to catecholamine

    Myocardial contraction

    Alleviate Accelerate

    myocardial lesion heart failure


Signal transduction and the related disorders

3. Aberrant G-protein

in Cell Signaling


Signal transduction and the related disorders

G-protein-Mediated Pathway


Signal transduction and the related disorders

Activation of Adenylate Cyclase by Gs


Signal transduction and the related disorders

GTPase

Regulation of G-Protein Activity


Signal transduction and the related disorders

G-protein gene mutation—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


Signal transduction and the related disorders

G-protein gene mutation—type 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


Signal transduction and the related disorders

G-protein modification——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


Signal transduction and the related disorders

4. Aberrant Intracellular Signaling


Signal transduction and the related disorders

Aberrant intracellular Signaling

Pro-carcinogen of phorbolester

PKC persistent activation

Growth factors

Cancer gene expression

Na+/H+ exchange 

Intracellular pH↑/ K+↑

Cell proliferation

(Cancer)


Signal transduction and the related disorders

Aberrant intracellular Signaling

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


Signal transduction and the related disorders

5.Multiple Abnormalities in Signaling Pathway


Signal transduction and the related disorders

The sympathetic regulation in heart failure

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


Signal transduction and the related disorders

cAMP

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


Signal transduction and the related disorders

Multifactor Aberrancies and Cancer

(Enhancement of proliferating signals)

  • Ligands (GFs)

  • Receptors (overexpression, activation of TPK)

  • Intracellular transducers:

    Ras mutation Ras-GTPase Ras activation

    Raf MEK ERK Proliferation TUMOR


Signal transduction and the related disorders

Multifactor Aberrancies and Cancer

(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


Signal transduction and the related disorders

6. Same Stimulant Induces Different Responses

(the same stimuli can act on different receptors)


Signal transduction and the related disorders

Infectious Shock

-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


Signal transduction and the related disorders

7. Different Signals Induces the Same Pathologic Response

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


Signal transduction and the related disorders

Different receptors use same pathways

GPCR, RTKR, Cytokines Rs

PLC Ras PI-3K

PKC Raf PKB

MEK

ERK


Signal transduction and the related disorders

Cross talk—how 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

Myocardial Hypertrophy


Signal transduction and the related disorders

9. Principles for Treatment of Aberrant Signaling-related Diseases


Signal transduction and the related disorders

Principles for Treatment

  • 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


Signal transduction and the related disorders

LPS

TNF

IL-1


Signal transduction and the related disorders

Regulating of signal transduction

in treatment of diseases


Signal transduction and the related disorders

10. Application of Signal Transduction in Scientific Research


Signal transduction and the related disorders

Regulating Signal Transduction in 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


Signal transduction and the related disorders

Mutation

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?


Signal transduction and the related disorders

Dominant negative effect?

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


  • Login