Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat the University of Pécs and at the University of DebrecenIdentification number: TÁMOP-4.1.2-08/1/A-2009-0011

INTRODUCTIONPART 2

Tímea Berki and Ferenc BoldizsárSignal transduction

Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat the University of Pécs and at the University of DebrecenIdentification number: TÁMOP-4.1.2-08/1/A-2009-0011

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Plasma membrane

Nucleus

Receptor

Cytoplasm

Signal

Chaperoneprotein

Outside of cell

Inside of cell

Intracellular receptor signaling

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Ligands binding to intracellular receptors

CortisolO

HOOHOC

CH2OH

Retinoic acidCH3

CH3CH3 CH3H3C O

OHC

O

OHCHO

I

I

I

I

O CH2 CH

NH2

Thyroxine

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Steroid receptor superfamily

DNA bindingdomain (≈68 aa)

Ligand binding domain (≈225-285 aa)

553 Estrogen receptor

946 Progesterone receptor

777 Glucocorticoid receptor

408 Thyroid hormone receptor

432 Retinoid acid receptor

COOHNH2 General primary structure

Variable region(≈100-500 aa)

Amino acididentity 0% 42-94% 15-57%

1

1

1

1

1

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Glucocorticoid receptor phosphorylationGR phosphorylation sites:• Thr171 – Glycogen synthase kinase-3 (GSK-3)• Ser 224 and 232 – Cyclin-dependent kinases (CDK)• Ser246 – JNK• Thr547 – p38 - MAPK → GCR inhibition

1 2 3 4

5

Thr171

Thr547

Ser224

Ser232

Ser246

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Slow Medium slow Rapid

Transmembrane currentsPhosphorylation events

Calcium levels

Plasma membrane

Cytoplasm

Glucocorticoid mGR

cGR

Specific cGRdependent effects

Specific mGRdependent effects Nonspecific GC

effects

GRE

TF

nGRE pGRE

Transrepression Transactivation

Genomic GC effects Nongenomic GC effects

IL-2 IkBSTATNFkB TCR

MAPK

GC hormone mechanisms

TÁMOP-4.1.2-08/1/A-2009-0011Hormones are classified into three categories based on their structure • Peptides: Comprises most hormones, including those

secreted by the hypothalamus, anterior and posterior pituitary, pancreas and parathyroid.

• Amines: Derived from the amino acid, tyrosine, and include the hormones secreted by the thyroid gland, and adrenal medulla. Adrenomedullary hormones are called catecholamines.

• Steroids: Neutral lipids derived from cholesterol; include hormones secreted by the adrenal cortex, ovaries and testes. Steroid and thyroid hormones are lipid soluble (lipophilic).

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Primary hormone-secreting glands • Pituitary gland (anterior pituitary) secretes GH which

is a protein stimulating protein synthesis and growth (depression at bottom of skull just over back of roof of mouth)

• Hypothalamus• Pineal gland secretes melatonin, a modified amino

acid to hypothalamus for sleep

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The other hormone-secreting glands are: • Sex organs (gonads)

– Ovaries: androgens and progesterones– Testes: androgens

• Adrenal glands– Adrenal medulla secretes epinephrine, norepinephrine, modified

amino acids stimulate fight-or-flight response (increase heart, redistribute blood to muscles, raise blood sugar)

– Adrenal cortex secretes glucocorticoids (cortisol), steroids targeting muscles, immune system, and other tissues to mediate response to stress, reduce metabolism of glucose, increase metabolism of proeins and fats, reduce inflammation and immune responses

• Thyroid gland secretes calcitonin, which is a peptide acting on bones to stimulate bone formation and lower blood calcium, parathyroid raises blood calcium

• Pancreas secrets insulin and glucagon

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Other Chemical messengers• Cytokines• Interferons are proteins released when a cell has been

attacked by a virus. They cause neighboring cells to produce antiviral proteins. Once activated, these proteins destroy the virus

• Prostaglandins are fatty acids that behave in many ways like hormones. They are produced by most cells in the body and act on neighboring cells

• Pheromones are chemical signals that travel between organisms, rather than between cells within an organism. In the animal world, pheromones are heavily used to mark territory, signal prospective mates and to communicate. The presence of a pheromone as a human sex attractant has not been established

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Basic characteristics of cytokines• Low molecular weight (10-40 kDa) glycoproteins• Isolated cells secrete them, due to gene activation• They mediate cell-cell interaction:

– Sending information– Regulation of immune response

• Mechanism of action:– Produced after transient gene activation– Act through receptors triggering signal

transduction– High affinity– Picomolar concentration

• They act mostly locally

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Environmental stimuli as signal initiators• Microbial products: viral nucleotides, bacterial

lipopolysaccharides stimulate TLR, and protein antigens B cell and T cell receptors

• Physical stimuli: light striking cells in the retina of the eye, odorants binding to odorant receptors in the nasal epithelium, bitter and sweet tastes stimulating taste receptors in the taste buds

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Toll-like receptors (TLRs)• They are single, membrane-spanning, non-catalytic

receptors that recognize structurally conserved molecules derived from microbes.

• They receive their name from their similarity to the protein coded by the Toll gene identified in Drosophila in 1985 by Christiane Nüsslein-Volhard. The gene in question, when mutated, makes the Drosophila flies look unusual, or 'weird'. The researchers were so surprised that they spontaneously shouted out in German "Das ist ja toll!" which translates as "That´s wild„.

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MyD88 TRIF

TLR3TLR7

TLR2

PKA TAK1 PKR

p38 JNK

MKKs lkBp50

p65

MyD88

LPS

TLR4

MyD88

MD2LBP

dsRNA

TBK1IKKe

MDA-5RIG-1

IPS1

TLR9JAK2

mTOR

PI3K

CD14

TLR types