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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 HO CH3 O OH Retinoic acid 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 Estrogen receptor 553 1 1 1 1 946 Progesterone receptor 777 Glucocorticoid receptor 408 Thyroid hormone receptor 1 Retinoid acid receptor 432 NH2 COOH Variable region (≈100-500 aa) Amino acid identity 0% DNA binding Ligand binding domain (≈68 aa)domain (≈225-285 aa) 42-94% 15-57% General primary structure TÁMOP-4.1.2-08/1/A-2009-0011 Glucocorticoid receptor phosphorylation GR phosphorylation sites: • Thr171 – Glycogen synthase kinase-3 (GSK-3) • Ser 224 and 232 – Cyclin-dependent kinases (CDK) • Ser246 – JNK Ser • Thr547 – p38 232 - MAPK → GCR inhibition Thr 171 1 Ser 224 2 3 Ser 246 4 5 Thr 547 TÁMOP-4.1.2-08/1/A-2009-0011 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 Hormones are classified into three categories based on their structure TÁMOP-4.1.2-08/1/A-2009-0011 • 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 TÁMOP-4.1.2-08/1/A-2009-0011 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 TÁMOP-4.1.2-08/1/A-2009-0011 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 TÁMOP-4.1.2-08/1/A-2009-0011 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 TÁMOP-4.1.2-08/1/A-2009-0011 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 TÁMOP-4.1.2-08/1/A-2009-0011 Toll-like receptors (TLRs) • They are single, membrane-spanning, noncatalytic 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„. TÁMOP-4.1.2-08/1/A-2009-0011 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 MKKs PKR p50 lkB p65 p38 JNK TBK1