Signal Transduction and the Related Disorders

The process in which cells sense the extracellular stimuli through membranous or intracellular receptors, transduce the signals via intracellular molecules, and thus regulate

the biological function of the cells

Basic Concept of Cell Signaling(trans-membranous 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

Major pathways for cell signaling

Aberrant Cell Signaling and the Related Disorders

General process for transmembrane signal transduction

1. Aberrant Signal

Types of cellular signals

(1) Physical signals Light, electronic, mechanic, UV, heat, v

olume or osmotic, etc

(2) Chemical signals Hormones, neurotransmitters, GFs, cyt

okines; 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

ischemia, epilepsy, neurodegenerative diseases

extracellular glutamate/aspartic acid

NMDAR activation

Ca2+ influx

[Ca2+]i , activation of enzymes

excitatory intoxication

Aberrant Signal (Signal Excess)

Lesions in pancreatic -cell

Decreased insulin production

hyperglycemia

Diabetes (Type I)

Aberrant Signal (Signal Insufficiency)

Binding of TSH to R↓

hypothyroidism

Aberrant Signal (autoimmune-thyropathy)

Blocking Ab

TSH-R295~302385~395

AA residues

Gs

AC

cAMP

Thyroid proliferation & secretion

Gq

PLC

IP3 DG

Ca2+ PKC

TSH-R30~35aaresidues

Stimulatory Ab

hyperthyroidism

2. Aberrant Receptor in Cell Signaling

• Receptor gene mutation• Receptor down regulation or desensitization

Receptor Gene Mutation — Genetic insulin-resistant diabetes

IR gene mutations

Disturbances in synthesis in transfer to the membrane

in affinity to insulin in RPTK activation

in proteolysis

Type II Diabetes

Insulin+R

Activate RPTK

IRS

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

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)

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

Phosphatidylinositol 3-hydroxy kinase, makes PIP2,PIP3

Grb2, Sos, activates Ras

Activation of PLC

Receptor Tyrosine Kinases

Receptor Gene Mutation (NDI)

ADH + ADHV2-R

cAMP

AQP2 moves to lumen side in collecting tubules

Permeability↑

H2O absorption

Gene mutation

ADH reaction in collecting tubules↓

Diuresis

Gs V2R synthase↓

or affinity↓

Nephrogenic Ddiabetes

Insipidus

Myocardial hypertrophy

-R1 down regulated or desensitized

Reaction to catecholamine

Myocardial contraction

Alleviate Accelerate myocardial lesion heart failure

Secondary Abnormality in Receptors(Heart failure)

3. Aberrant G-proteinin Cell Signaling

G-protein-Mediated Pathway

Activation of Adenylate Cyclase by Gs

GTPase

Regulation of G-Protein Activity

G-protein gene mutation—pituitary tumor

Gs gene mutation

GTPase activity

Persistent activation of Gs

Persistent activation of AC

cAMP

Pituitary proliferation and secretion

GHRH

Pituitary

Gs

GH

Acromegaly or Gigantism

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 gene mutation—type 1A-PHP

G-protein modification——cholera

Cholera toxinGs ribosylation at Arg201

Inactivation of GTPasePersistent activation of Gs and cAMP

Conformational alteration of intestinal epitheliaCl- and H2O to lumen of intestine

Diarrhea and dehydration

Circulation failure

4. Aberrant Intracellular Signaling

Pro-carcinogen of phorbolester

PKC persistent activation

Growth factors

Cancer gene expressionNa+/H+ exchange

Intracellular pH↑/ K+↑

Cell proliferation

(Cancer)

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

Aberrant intracellular Signaling

5. Multiple Abnormalities in Signaling Pathway

The sympathetic regulation in heart failure

Density of SN↓ ； tyrosine hydroxylase↓

β-R down regulated ；pH↓→ reaction of R to CA↓

Gs↓ ， function↓ ； Gi ， function

1R

cAMP

Gs

CA

Normal Hypertrophy, heart failure

SR pump↓

H+ inhibits binding of Ca2+ to troponin

SR phospholamban

Ca2+ pump

[Ca2+] i ↓

Myocardial dilation

cAMP

Ca2+channel

Ca2+ influx

SR Ca2+channel

[Ca2+] i

Myocardial contraction

Ligands (GFs) Receptors (overexpression, activation of TPK) Intracellular transducers ： Ras mutation Ras-GTPase Ras activation

Raf MEK ERK Proliferation TUMOR

Multifactor Aberrancies and Cancer

(Enhancement of proliferating signals)

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)

Lymphoma, liver cancer,

Stomach cancer

Gene mutation

Negative regulation

6. Same Stimulant Induces Different Responses

(the same stimuli can act on different receptors)

Excitatory sympathetic nerve stimuli

PLC

Gq

IP3 DG

Ca2+

CaMK

PKC

MLCK

Myosin

Artery Contraction

AC pathwayIP3/DG pathway

KCa2+Ca2+pump

[Ca2+]i

-R β-R

Gs

AC

cAMP

PKA

A-V shunt

Infectious Shock

7. Different Signals Induces the Same Pathologic Response

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

Different receptors use same pathways

GPCR, RTKR, Cytokines Rs

PLC Ras PI-3K

PKC Raf PKB

MEK

ERK

Cross talk—how hypertension leads to myocardial hypertrophy?

NE, AT-II

PLC

Ca2+/PKC

Mechanic stimuli

Na+, Ca2+ influx

Na+-H+ exchange

MAPK

Transcription factors

Myocardial Hypertrophy

GF TGF-

TPK PSTK

Raf

Ras Smad-PAlkalization

9. Principles for Treatment of Aberrant Signaling-related 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

Principles for Treatment

LPSTNFIL-1

Regulating of signal transduction in treatment of diseases

10. Application of Signal Transduction in Scientific Research

PI3-K

S473

InactivePKB

T308

PDK1/PDK2

ActiveGSK-3/

S9/21

P

P

WT

Normal tauPP AD p- tauP P

PP P

PP P

P

P

PKC

Caspase-3

InactiveGSK-3/

S9/21

PP

GF-109203X

ActiveGSK-3/

S9/21

Normal tauPP

P P

PP P

PP P

P

P

AD p- tau

Regulating Signal Transduction in 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

Mutation

Gain or loss of function mutations?

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