Classification of Receptors

Transcription

1 Classification of Receptors 1. G Protein coupled receptors epinephrine, serotonine, glucagon 2. Ion channel receptors acetylcholine receptor 3. Tyrosine kinase-linked receptors cytokine-receptor family 4. Receptors with intrinsic enzymatic activity the receptor has intrinsic catalytic activity receptor tyrosine kinases

2 Receptors with intrinsic enzymatic activity 1. Guanylatcyclase: GTP -> cgmp ANP: peptide hormone, atrium of the heart upon Upon rising blood pressure decreases vascular resistance via a cgmp dependent kinase 2. serin-threonine kinases: TGF ß superfamily growth inhibition, bone formation, 3. receptor tyrosine phosphatases: CD45, expressed on B and T lymphocytes 4. RTKs: EGFR, Insulin, VEGFR

3 The ANP Receptor

4 Receptors with intrinsic enzymatic activity 1. Guanylatcyclase: GTP -> cgmp ANP: peptide hormone, atrium of the heart upon rising blood pressure decreases vascular resistance via a cgmp dependent kinase 2. serin-threonine kinases: TGF ß superfamily growth inhibition, bone formation, 3. receptor tyrosine phosphatases: CD45, expressed on B and T lymphocytes 4. RTKs: EGFR, Insulin, VEGFR

5 CD45 exists in various isoforms cell type specific glykosylation B220 B cell specific D1: active phosphatase highly conserved D2: inactive required for correct folding

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7 Constitutive activation of CD45 leads to lymphoproliferation and autoimmunity in mice Cell 2000, 103: 1059

8 Inactivation of CD45 leads to Severe combined Immuno Deficiency (SCID) The hematopoietic-specific transmembrane protein tyrosine phosphatase CD45 functions to regulate Src kinases required for T- and B-cell antigen receptor signal transduction. So far, there have been no reports to our knowledge of a human deficiency in a tyrosinespecific phosphatase. Here, we identified a male patient with a deficiency in CD45 due to a large deletion at one allele and a point mutation at the other. The point mutation resulted in the alteration of intervening sequence 13 donor splice site. The patient presented at 2 months of age with severe combined immunodeficiency disease. The population of peripheral blood T lymphocytes was greatly diminished and unresponsive to mitogen stimulation. Despite normal B-lymphocyte numbers, serum immunoglobulin levels decreased with age. Thus, CD45 deficiency in humans results in T- and B-lymphocyte dysfunction. Nature Med 2000, 6:343

9 Implications for Medicine Inhibitors of CD45 have implications in transplant medicine prevention of kidney rejection in mouse models has been proven microglial activation by ß-amyloid peptide can be prevented Alzheimers disease the various specific activatio forms may allow for a relatively specific inhibition dependent on the indication

10 RTKs NGF, PDGF, FGF, EGF, Insulin regulate cell survival, proliferation, differentiation therefore found in cancer constitutive active RTKs RTKs-ras as important signalling cascade leading to cancer

11 ligand binds a dimer dimerization of the receptor activation of its kinase activity tyrosine phosphorylation of its own cytosolic domaine

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14 RTKs are frequent targets in human cancer

15 Signalling Pathways in Cancer downstream of RTK

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17 Sorafenib Hemmt Serin/Threonin- und Rezeptor-Tyrosinkinasen = Multikinasenhemmer Greift in RAS-Signasltransduktionsweg ein, indem er RAF-Kinase (= Serin/Threonin-Kinase) hemmt verminderte Proliferation von Tumorzellen Hemmt VEGF-Rezeptor keine Angiogenese keine Nährstoffversorgung kein Wachstum Hemmt PDGFR (Platelet-derived growth factor) Hemmt c-kit (stem-cell growth factor)

18 ErbB Protein Tyrosine Kinase Subfamily EGF, TNFα, ΗΒ ΕΓΦ Heregulin, NDF.. dual cysteine cluster tyrosine kinase domain EGFR ErbB1 HER2 ErbB2 neu HER3 ErbB3 HER4 ErbB4

19 EGFR/ErbB2 Heterodimer NH 2 EGFR/ErbB1 ErbB2/HER2 membrane COOH P P P P P P P Tyr877 Tyr1023 Tyr1112 Src Tyr1139 Tyr1196 Tyr1221 Tyr1248 Cbl Grb2 Shc Chk GTP Sos Ras GDP Raf1 MEK MAPK Sustained MAPK activation: G 0 / G 1 progression, differentiation

20 Herceptin efficently inhibits Her2 signalling in breast cancer

21 The EGFR a key element in receptor cross-talk: signal transactivation

22 GPCR activates metalloproteinases The ADAMS

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24 The IGF-receptor a key molecule in cancer

25 Oncogenes that need an intact IGF-R signalling

26 VEGF VEGF is a homodimeric glycoprotein, binding to VEGF-Receptors on vaskular endothelial cells Molecular weight: 45,000Da VEGF plays a key role for the formation of blood vessels (Angiogenesis) VEGF = vascular endothelial growth factor Ferrara N, et al. Endocr Rev 1997;18:4 25

27 Die VEGF Familie und ihre Rezeptoren VEGF-A VEGF-B PlGF VEGFR-1 VEGF-A VEGFR-2 VEGF-C VEGF-D VEGFR-3 P P P P P P P P P P P P Migration, proliferation, permeability, DNA synthesis, survival Angiogenesis Lymphangiogenesis Adapted from Ferrara N. Nat Med 2003;9:669 76

28 Angiogenesis contributes to Tumorigenesis, tumor growth and Metastasis Prämalignes Stadium Maligner Tumor Tumor- Wachstum Gefäßinvasion ruhende Mikrometastase Offene Metastasierung (Avaskulärer Tumor) (Angiogenic switch) (Vaskularisierter Tumor) (Tumorzellfreisetzung) (Streuung in entfernte Organe) (Zweite Angiogenese) Schritte, bei denen Angiogenese eine Rolle bei der Tumorprogression spielt Modifiziert nach Poon RT-P, et al. J Clin Oncol 2001;19:

29 The angiogene switch and Tumordevelopment Kleiner Tumor (1 2mm) avaskulär ruhend größerer Tumor vaskularisiert Metastasierungspotential Angiogenic switch führt zur Überexpression von pro-angiogenen Faktoren, wie zum Beispiel VEGF Modifiziert nach Bergers G, et al. Nat Rev Cancer 2002;3:401 10

30 VEGF overexpression correlates with a bad prognosis Study Cancer n Tumours (%) Prognostic value Gasparini, 1997 Breast Relapse-free survival, overall survival Toi, Increased vascular density and relapsefree survival Imoto, 1998 Lung NSCLC Overall survival O Byrne, 2000 NSCLC Tumour size, vascular density Volm, 1997 SCLC Overall survival Maeda, 2000 GI CRC Overall prognosis Amaya, 1997 CRC Vascular density Ishigami, 1998 CRC Clinical stage, metastasis Ogata, 2003 Oesophagus Overall survival Shih, 2000 Oesophagus Overall survival Paley, 1997 Ovarian Disease-free survival Yamamoto, Overall survival Jacobsen, 2004 Renal Tumour size and stage, survival Aguayo, 2002 Haem. AML Survival Verstovsek, 2002 Haem. CML Survival

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32 Antiangiogenic therapy a double edged sword