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Mechanisms of Hormone Action: Peptide Hormones

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Mechanisms of Hormone Action: Peptide Hormones Frontiers in Reproductive Endocrinology Serono Symposia International Mechanisms of Hormone Action: Peptide Hormones Kelly Mayo Northwestern University Mechanisms of Cell Communication Endocrine Signaling Paracrine Signaling Autocrine Juxtacrine Signaling Signaling Endocrine Signaling 1 Emergence of Key Concepts in Hormone Action Berthold, 1849 Starling, 1905 Castrated cockerels and Stimulation of pancreatic restored male sex enzyme secretion by characteristics by replacing humoral factor (secretin) testes in the abdomen from intestinal extracts “Endocrinology” “Hormone” Langley, 1906 Sutherland, 1962 Action of nicotine and Glycogen metabolism and curare on the ‘receptive hormonal activation of substance’ of the liver phosphorylase neuromuscular junction enzyme by cAMP “Receptor” “Second Messenger” Structural Diversity in Reproductive Hormonal Signaling Molecules pyroGlu His Trp Ser HOOC OH Tyr Gly OH Leu N O Arg HO H Pro O OH Gly GlyNH2 FSH GnRH Estradiol PGF2a Nitric Oxide Protein Peptide Steroid Eicosanoid Gas 203 aa 10 aa MW 272 MW 330 MW 30 2 Measuring Receptor-Ligand Interaction ka R (receptor) + H (hormone)! ! RH (complex) Total Binding kd Specific Binding Ka = [RL] Kd = [R][L] ! [R][L] ! [RL] (units are moles -1) (units are moles) Nonspecific Binding Fractional Binding Total R, RT= [R] + [RL], so: Kd = [RT-RL][L] [Hormone] [RL] Rearrange to: [L] = [RL](Kd + [L] [RT] ~Kd Fraction of receptor [RL] = [L] = 1 ocupied by ligand: [RT] Kd + [L] 1 + Kd ! ! ! ! [L] Fractional Binding At 50% occupancy (1/2), Kd = [L] log [Hormone] General Mechanisms of Action of Steroid and Peptide Hormones Steroid Protein P Hormone S Diffuses across Hormone Binds to cell plasma membrane surface receptor P Hormone-activated receptor S Receptor-associated Activation of effector Non-genomic changes in enzyme activity enzymes S effects via Cytoplasmic or protein -protein Generation of nuclear receptor Binds to DNA interaction second messengers in target genes Biological output Changes in Changes in enzyme activity Regulates enzyme activity Activation of gene transcription S transcription factors Biological P TF P output Biological New mRNAs output New mRNAs Synthesis of new proteins Synthesis of new proteins Biological Biological output output 3 Major Classes of Peptide Hormone Receptors G Protein-Coupled Receptors Largest family (>800), Highly Diverse Receptor Tyrosine Kinases “Growth Factor” Receptors Receptors that Recruit Tyrosine Kinases Cytokine Receptors/Stat Pathway Receptor Serine/Threonine Kinases TGFb/Smad Pathway Developmental Pathway Receptors Hedgehog/Wnt/DSL Ligands “Other Pathways” Diverse and Growing Families of G Protein-Coupled Receptors Family A: Rhodopsin-Like Rs Group I: Olfactory, Adenosine, Melanocortin Rs Group II: Adrenergic, Muscarinic, Serotonin, Dopamine Rs Group III: Neuropeptide Rs and Vertebrate Opsins Group IV: Bradykinin Rs and Invertebrate Opsins Group V: Peptide, Glycoprotein Hormone and Chemokine Rs FSH,LH, Relaxin, Group VI: Melatonin and Orphan Rs GnRH Receptors Family B: Secretin-Like Rs Family C: Glutamate-Like Rs Group I: Calcitonin and CRF Rs Group I: Metabotropic Glutamate Rs Group II: PTH and PTHrP Rs Group II: Calcium Sensing Rs Group III: Glucagon, Secretin, VIP, GHRH Rs Group III: Vertebrate Pheromone Rs Family D: Fungal Pheromone Rs Family E: cAMP Rs Group I: Alpha Factor Pheromone Rs Group I: Dictyostelium cAR Rs Group II: A Factor Pheromone Rs Frizzled/Smoothened Rs Group I: Frizzled Rs Group II: Smoothened Rs 4 Features of a Prototypical G Protein-Coupled Receptor (GPCR), the b-Adrenergic Receptor Glycosylation -NH2 Agonist Binding Antagonist Binding TMD1 TMD2 TMD3 TMD4 TMD5 TMD6 TMD7 Palmitoylation P P PKA Phosphorylation Required for Catacholamine Binding and Activation Asp 113 Ser 204,207 G Protein Coupling COOH- P P P P P P bARK Phosphorylation Structure of a G Protein-Coupled Receptor, Rhodopsin Cytoplasmic View Membrane-Parallel View Extracellular View Palczewski et al, Science 289: 739, 2000 5 Pathways of G Protein-Coupled Receptor Action Receptor G AC as g GDP Adenylyl Cyclase b (Effector) Heterotrimeric H G protein H Ga Ga ATP AC s g AC s g GTP GTP Arrestins b P P H b cAMP Second Messenger G ATP AC as g Gas GTP GRK GDP Receptor P P b Internalization GTP Pathways cAMPcAMP Hydrolysis RR + PKA ATP P Substrate Phosphorylation Diversity and Specificity in G Protein Signaling Multiple Receptors Activate One Receptor Activates the Same G Protein Multiple G Proteins b b a b a b a a b g g g g g Diverse Actions of G Protein Receptor Specificity G Protein Heterotrimers Carbachol Somatostatin a Signaling Diversity (Gs, Gi, Gq,Go) a and bg Effector Activation M4R SSR Combinatorial Assembly Go1b3g4 Go Go2b1g3 20 a, 6 b, 12 g=1440 Heterotrimers Ca++ Channel Kleuss et al, Nature 353:43, 1991 6 Current Issues in G Protein Coupled Receptor Research Receptor Trafficking Receptor Signaling Internalization Desensitization GRK Kinases RGS Proteins RAMP Proteins Non G protein pathways Receptor Diversity Receptor Structure Dimerization Molecular Modeling Alternative Splicing G Protein Interaction Modifications Structure Determination Therapeutics Ligand Mimics Altered Regulation Orphan Receptors New Pathways Receptors with Intrinsic Kinase Activity or Associated with Kinase Activity General Features Type I Integral Membrane Proteins Dimerization Critical to Activation Receptor Phosphorylated on Activation Signaling Proteins Bind to Phosphorylated Receptor Proteins that Suppress Signaling Receptor that are Tyrosine Kinases Growth Factor Receptors Insulin Receptor Receptors that Recruit Tyrosine Kinases Cytokine Superfamily Receptors Prolactin Receptor Receptors that are Serine/Threonine Kinases TGFb Superfamily Receptors MIS Receptor 7 Receptors that are Protein Tyrosine Kinases Examples of RTK Families EGFR PDGFR InsulinR RET EGF Receptor Subfamily NGFR (EGFR, HER2/Neu) NGF Receptor Subfamily (TrkA, TrkB, TrkC) SS SS FGF Receptor Subfamily (FGFR1-4, Cek2) HGF Receptor Subfamily (HGFR=MET) PDGF Receptor Subfamily (PDGFR a/b, VEGFR) Insulin Receptor Subfamily (InsulinR, IGF-1R) Tyrosine Kinase Domain EPH Receptor Subfamily (Ephrin AR, Ephrin BR) Cysteine-rich Domain ROR Receptor Subfamily Immunoglobulin Domain (RET-GDNF) Cadherin Domain Receptor Tyrosine Kinase Signaling Pathway Hormone RTK Signaling Ligand-induced dimerization P P K K K GTP Receptor phosphorylation Receptor Dimerized sos Monomer Activated grb2 ras Effector proteins bind receptor Receptor raf - direct enzymatic function P - adaptor proteins MAPK Phosphatases Initiation of kinase cascades P MEK MEK Changes in gene expression MAPK Phosphatases and negative regulation P Transcription Factor P Gene Expression RE 8 Receptors that Associate with Cytoplasmic Kinases Families of Cytokine Receptors PRL-R LIF-R IL-3-R INFg-R Type I: Single chain (GH, PRL, EPO, TPO) Type II: Shared gp130 signaling subunit (IL-6, LIF, IL-11, CNTF) Type III: Shared gp140b, ligand-specific a (IL-3, IL-5, GMCF) Type IV: Shared gc, ligand-specific a R1 (HGFR=MET) Type V: Two or more distinct subunits R2 (IFNa/b, IFNg) gp130 Janus Family Kinases bC Jak1 (IL-2, IL-6, GCSF, INFa/b, INFg) Jak2 (GH, PRL, EPO, IL-5) Jak3 (IL-2. IL-4, IL-7) Stat DBD SH3 SH2 TAD Tyk2 (IL-6, LIF, INFa/b) JAK Kinase Stat Proteins Stat DBD SH3 SH2 TAD Stats 2 and 6 Stats 1, 3, 4, 5A, 5B P P Cytokine Receptor Signaling Pathway Hormone Cytokine Signaling Ligand-induced dimerization Box 1 JAK JAK 2 K K 2 P P Receptor association with Receptor Binding Dimerized JAK kinase Monomer to Site 1 Activated P P Receptor Receptor phosphorylation P STAT Stat Dimer Effector proteins bind receptor SOCS - direct enzymatic function P P STAT - STAT proteins STAT Dimer STATs phosphorylated STATs dimerize STATs migrate to the nucleus P P Gene Changes in gene expression Expression GAS SOCS proteins and negative regulation 9 Prolactin-Induced Receptor Dimerization Biological + Response Increasing Prolactin Increasing Prolactin oPL-Receptor Complex Receptor Interaction Sites on oPL Elkins et al, Nature Structural Biology 7:808, 2000 Receptors with Serine/Threonine Kinase Activity Ligand Type II Type I Ligand Receptor Receptor TGF-b TbR-II TbR-I Activin ActR-IIB ActR-IB GS Box MIS AMHR ActR-I TTSGSGSG BMP2 BMPR-II BMPR-IA Kinase Domain BMP7 ActR-II BMPR-1B GDF5 ActR-IIB ActR-I Type II Type I Dpp Punt Tkv, Sax Receptor Co- Inhibitory MH1 MH2 SSXS Smads Smads Smads Receptor 1,2,3,5,8 Smad 4 Smads 6,7 Kinase Mad Medea Dad P P Sma2,3 Sma-4 MH1 MH2 SSXS 10 Serine/Threonine Receptor Signaling Pathway Hormone TGFb Family Signaling II I II I Ligand binds to type II receptor K P P K K I K Dimerized Type I and II receptor associate P Activated Receptor- Receptor P Smad Type II Type I (1,2,3,5,8) Type I receptor phosphorylation Receptor Receptor Inhibitory Effector proteins bind receptor Hetero-Oligomer P P - direct enzymatic function P Smad (6,7) - Smad proteins P P P Smads phosphorylated Co-Smad (4) Smads heterodimerize Smads migrate to the nucleus FAST-1 Smads bind other TFs P P Other P Changes in gene expression Gene Expression T/ARE Inhibitory Smads and negative regulation Some Key Developmental Signaling Pathways Ligand Receptor To Nucleus Partner Comments Delta/Serrate/ Notch Notch CSL Receptor proteolysis Lag2 (Cytoplasmic CSL Repressor to Activator Domain) Wnt Family Frizzled b-catenin LEF/TCF b-catenin stabilized TCF Repressor to Activator Hedgehog Patched Ci/Gli CBP Patched/Smoothened Complex (Shh,Dhh,Ihh) (Full-Length) Ci-75 Repressor in Basal State Notch: Oogenesis in Drosophila (expressed in mammalian ovary) Notch2: Placental
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