TRANSDUCTION DU SIGNAL. Messagers intracellulaires Couplage aux protéines G Transmission via la voie des MAP kinases Transmission via la voie du NO
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1 TRANSDUCTION DU SIGNAL Messagers intracellulaires Couplage aux protéines G Transmission via la voie des MAP kinases Transmission via la voie du NO
2 TRANSDUCTION DU SIGNAL - MESSAGERS INTRACELULAIRES
3 TRANSDUCTION DU SIGNAL LONG TERME ADAPTIVE RESPONSE From Principles of neuropsychopharmacology; 1997; pp224, 226
4 Messager AMPc GMPc Ca 2+ IP3 DAG Acide phosphatidique Céramide NO ADP-ribose c Source Adenylate cyclase Guanylate cyclase Canaux ioniques du RE et de la membrane plasmique Action de PLC sur PI Action de PLC sur PI Action de PLD Action de PLC sur SM NO synthase ADP-ribose synthase Effets Active les protéines kinases Active les protéines kinases Régule des canaux ioniques Régule des phosphodiestérases Active des protéines kinases Active des protéines à fonctions modulées par le calcium Active les canaux calciques Active la protéine kinase C Active les canaux calciques Inhibe l adénylate cyclase Active les protéines kinases Active la guanylate cyclase Stimule la relaxation des muscles lisses Active les canaux calciques
5 TRANSDUCTION DU SIGNAL - COUPLAGE AUX PROTEINES G Système d amplification Un unique complexe agoniste-récepteur peut activer plusieurs protéines G dont chacune s associera à une enzyme effectrice pendant un temps suffisamment long pour produire de nombreuses molécules
6 G-PROTEIN-COUPLED RECEPTORS DIVERSITY Marinissen and Gutkind 2001, 22:
7 TRANSDUCTION DU SIGNAL - COUPLAGE AUX PROTEINES G From Principles of neuropsychopharmacology Ed. Feldman, Meyer and Quenzer Sinauer Ass., Inc., Publish., 1997; pp210
8 TRANSDUCTION DU SIGNAL - COUPLAGE AUX PROTEINES G
9
10 TRANSDUCTION DU SIGNAL - COUPLAGE AUX PROTEINES G
11 TRANSDUCTION DU SIGNAL - COUPLAGE AUX PROTEINES G - Adenylate cyclase
12 TRANSDUCTION DU SIGNAL - COUPLAGE AUX PROTEINES G Hormones that activate or inhibit adenylate cyclase Activators Corticotropin (ACTH) Calcitonin Catecholamines (acting on ß1 and ß2 receptors ) Choriogonadotropin Follicle-stimulating hormone (FSH) Glucagon Gonadotropin-releasing hormone (GnRH) Growth hormone-releasing hormone Luteinizing hormone (LH) Inhibitors Angiotensin Catecholamines (acting on α 2 receptors) Lipotropin Melanocyte-stimulating hormones (MSH) Parathormone (PTH) Secretin Thyrotropin regulatory hormone (TRH) Thyrotropin (TSH) Vasoactive intestinal peptide (VIP) Vasopressin
13 TRANSDUCTION DU SIGNAL - COUPLAGE AUX PROTEINES G - Adenylate cyclase From Principles of neuropsychopharmacology Ed. Feldman, Meyer and Quenzer Sinauer Ass., Inc., Publish., 1997; pp210
14 TRANSDUCTION DU SIGNAL - COUPLAGE AUX PROTEINES G - Adenylate cyclase Simmonds 1999 TiPS 20: 66-73
15 TRANSDUCTION DU SIGNAL - COUPLAGE AUX PROTEINES G - Adenylate cyclase - isoforms Simmonds 1999 TiPS 20: 66-73
16 TRANSDUCTION DU SIGNAL - COUPLAGE AUX PROTEINES G - AMP cyclique
17 TRANSDUCTION DU SIGNAL - COUPLAGE AUX PROTEINES G - Phospholipase C
18 TRANSDUCTION DU SIGNAL - COUPLAGE AUX PROTEINES G - Phospholipase C
19 TRANSDUCTION DU SIGNAL - COUPLAGE AUX PROTEINES G PI, PIP 2, DAG AND IP 3
20 PROTEINES G ET RECEPTEURS COUPLES AUX PROTEINES G - POTENTIALITES THERAPEUTIOQUES Marinissen and Gutkind 2001, 22:
21 TRANSDUCTION DU SIGNAL - PROTEINES G ET VOIE DES MAPK Marinissen and Gutkind 2001 TiPS, 22:
22 TRANSDUCTION DU SIGNAL ET RECEPTEUR TYROSINE KINASE - VOIE DES MAPK
23 TRANSDUCTION DU SIGNAL - RECEPTEUR TYROSINE KINASE ET VOIE DES MAPK
24 TRANSDUCTION DU SIGNAL ET RECEPTEUR TYROSINE KINASE - VOIE DES MAPK
25 TRANSDUCTION DU SIGNAL ET CIBLE PHARMACOLOGIQUE - RECEPTEUR TYROSINE KINASE - VOIE DES MAPK Zwick et al TiPS : 17-23
26 RECEPTOR TYROSINE KINASE- EXTRACELLULAR SITE Binding of extracellular ligand DIMERIZATION Increase of receptor tyrosine kinase activity Zwick et al, Trends in Molecular Medicine (2002) 8: 17-23
27 RECEPTOR TYROSINE KINASE- INTRACELLULAR BINDING SITE Catalyse of recepteur autophosphorylation of cytoplasmic tyrosine residues Docking sites for Src homology (SH) and phosphotyrosine-binding (PTB) containing molecules (PLC, Src, ) Recrutment of additional effectors molecules containing SH2, SH3, PTB,PH (pleckstrin) domain Activation of a cascade of intracellular biochemical signals Zwick et al, Trends in Molecular Medicine (2002) 8: 17-23
28 ROLE PLAYED BY RECEPTOR TYROSINE KINASE IN CANCER Constitutive activation of receptor tyrosine kinase ~ malignant transformati on Zwick et al, Trends in Molecular Medicine (2002) 8: 17-23
29 TYROSINE KINASE RECEPTOR AS A CIBLE FOR CHEMOTHERAPY Zwick et al, Trends in Molecular Medicine (2002) 8: 17-23
30 MONOCLONAL ANTIBODIES AS ANTI- TYROSINE KINASE RECEPTOR DRUGS Anti-RTK mabs block the ligand-receptor interaction inhibition of ligand-induced RTK signaling increase of RTK down regulation and internalization Zwick et al, Trends in Molecular Medicine (2002) 8: 17-23
31 RECEPTOR TYROSINE KINASE -BASED DRUGS IN CLINICAL TRIALS - monoclonal antibodies Zwick et al, Trends in Molecular Medicine (2002) 8: 17-23
32 USE OF A MONOCLONAL ANTIBODY AGAINST HER2 (+ Chemotherapy) FOR METASTATIC BREAST CANCER Slamon et al, New Engl. J. Med (2001) 344:
33 INHIBITORS OF TYROSINE KINASE AS A CIBLE FOR CHEMOTHERAPY
34 RECEPTOR TYROSINE KINASE -BASED DRUGS IN CLINICAL TRIALS - Inhibitors of TRK
35 RECEPTOR TYROSINE KINASE INHIBITORS - Gefitinib - ZD STRUCTURE ATP analogues of the quinazoline/pyridopyrimidine family compete with ATP for the ATP binding site of the receptor tyrosine kinase domain.
36 RECEPTOR TYROSINE KINASE INHIBITORS ACTIVITY - ZD 1839 Antitumor activity volume tumor % of surviving mice of ZD-1839 on established GEO human colon carcinoma xenographs: effet dose Ciardiello et al (2000) Clin. Res. Cancer 6:
37 RECEPTOR TYROSINE KINASE INHIBITORS - Imatinib - STI 571 ATP analogues of the quinazoline/pyridopyrimidine family compete with ATP for the ATP binding site of the receptor tyrosine kinase domain.
38 Nature Medecine (2001) 7: 637
39 EFFICACY OF A SPECIFIC INHIBITOR (STI571) OF THE BCR-ABL TYROSINE KINASE IN CHRONIC MYELOID LEUKEMIA Immunoblot assays demonstrating the degree of phosphorylation of the BCR-ABL substrate CRKL in individual patients in the group receiving increasing dose of STI 571 From: Drucker et al, 2001 N. Engl. J. Med
40 IMMUNOTOXIN CONJUGATES AND LIGAND BINDING CYTOTOXIC AGENTS TO INHIBIT THE RECEPTOR TYROSINE KINASE SIGNALING Fusion/conjugaison between immunotoxins and specific ligand Binding to cell surface receptors Internalization into the endosome and translocation to the cytosol Inhibition of protein synthesis Zwick et al, Trends in Molecular Medicine (2002) 8: 17-23
41 RECEPTOR TYROSINE KINASE -BASED DRUGS IN CLINICAL TRIALS-Immunotoxin conjugates Zwick et al, Trends in Molecular Medicine (2002) 8: 17-23
42 TYROSINE KINASE RECEPTOR AS A CIBLE FOR CHEMOTHERAPY- Antisens oligonucleotide Antisens oligonucleotide interact with the RNAm to block the transcription and thus the expression of specific target proteins Zwick et al, Trends in Molecular Medicine (2002) 8: 17-23
43 ANTISENS OLIGONUCLEOTIDE AS RECEPTOR TYROSINE KINASE -BASED DRUGS IN CLINICAL TRIALS Zwick et al, Trends in Molecular Medicine (2002) 8: 17-23
44 TRANSDUCTION DU SIGNAL PROTEINE G ET VOIE DU NO
45 TRANSDUCTION DU SIGNAL ET NO PRODUCTION DU NO Garrett and Grisham, Biochimie, De Boeck, 2000, pg 1160
46 TRANSDUCTION DU SIGNAL ET NO PRODUCTION DU NO- NO SYNTHASE L hème essentiel à l activité de l enzyme est au centre de la partie concave du feuillet beta Garrett and Grisham, Biochimie, De Boeck, 2000, pg 1160
47 TRANSDUCTION DU SIGNAL ET NO
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