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Manifestation of Novel Social Challenges of the European Union
in the Teaching Material of
Medical Biotechnology Master’s Programmes
at the University of Pécs and at the University of Debrecen
Identification number: TÁMOP-4.1.2-08/1/A-2009-0011
Manifestation of Novel Social Challenges of the European Union
in the Teaching Material of
Medical Biotechnology Master’s Programmes
at the University of Pécs and at the University of Debrecen
Identification number: TÁMOP-4.1.2-08/1/A-2009-0011
Tímea Berki and Ferenc Boldizsár
Signal transduction
INTRODUCTION
PART 2
TÁMOP-4.1.2-08/1/A-2009-0011
Intracellular receptor signaling
Signal
Outside of cell
Plasma membrane
Cytoplasm
Receptor
Chaperone
protein
Nucleus
Inside of cell
TÁMOP-4.1.2-08/1/A-2009-0011
Ligands binding to intracellular
receptors
H3C
CH3
CH3
CH3
O
C
OH
CH2OH
C
CH3
O
OH
Retinoic acid
HO
I
O
HO
I
O
NH2
CH2
Cortisol
CH
O
C
OH
I
I
Thyroxine
TÁMOP-4.1.2-08/1/A-2009-0011
Steroid receptor superfamily
1
1
1
1
946
Progesterone receptor
777
Glucocorticoid receptor
408
Thyroid hormone receptor
Retinoid acid receptor
432
NH2
COOH
Variable region
(≈100-500 aa)
Amino acid
identity
Estrogen receptor
553
1
0%
DNA binding
domain (≈68 aa)
42-94%
Ligand binding
domain (≈225-285 aa)
15-57%
General primary structure
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Glucocorticoid receptor
phosphorylation
GR phosphorylation sites:
• Thr171 – Glycogen synthase kinase-3 (GSK-3)
• Ser 224 and 232 – Cyclin-dependent kinases (CDK)
• Ser246 – JNK
• Thr547 – p38 - MAPK → GCR inhibition
Ser
232
Thr
171
1
Ser
224
2 3
Ser
246
4
5
Thr
547
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GC hormone mechanisms
Nongenomic GC effects
Genomic GC effects
Glucocorticoid
mGR
Plasma membrane
Cytoplasm
cGR
Specific mGR
dependent effects
Nonspecific GC
effects
Specific cGR
dependent effects
STAT
NFkB
IL-2
IkB
TF
GRE
nGRE
Transrepression
Slow
pGRE
Transmembrane currents
Phosphorylation events
Calcium levels
Transactivation
Medium slow
Rapid
TCR
MAPK
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Hormones 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).
TÁMOP-4.1.2-08/1/A-2009-0011
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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TLR types
LPS
LBP
TLR2
TLR4
MD2
CD14
dsRNA
MyD88
MyD88
TLR9
TLR7
TLR3
RIG-1
JAK2
MDA-5
IPS1
PI3K
IKKe
mTOR
MyD88
PKA
TRIF
TAK1
PKR
MKKs
lkB
p50
p65
p38
JNK
TBK1