Lecture 7 (GH
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Lecture 7 (GH

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Lecture 7 (GH Lecture 7 (GH Presentation Transcript

  • MOLECULAR ENDOCRINOLOGY AND IMMUNOLOGY LECTURE 7 - Mechanism of action of growth hormone and prolactin Growth hormone : general actions; receptor; signal transduction; IGFs Prolactin : actions on mammary gland; other actions; receptor; signal transduction Mechanism of action of cytokines
  • The GH-IGF-Somatic axis
  • GH RECEPTOR
    • First cloned (as cDNA) from rabbit and then human liver (Leung et al 1987)
    Shown to be the “real” receptor by specificity, and absence in patients with Laron dwarfism signal extracellular transmembrane intracellular 0 247 620
  • Cytokine receptors
  • OVINE GH-RECEPTOR HOMOLOGY MODEL
  •  
  • GH-RECEPTOR INTERACTION
  • JAK Kinases Soluble tyrosine protein kinases, first named “just another kinase”. Subsequently “janus kinases” (because two apparent binding sites for ATP) JAK1 JAK2 JAK3 Tyk
  • GH Receptor and jak2 From: Herrington & Carter-Su (2001)
  • GH signalling From: Herrington & Carter-Su (2001)
  • STAT = signal transduction and activation of transcription STAT1-STAT5 In 3T3-F442A cells use of antisense knock-out of JAK2 or STAT5 eliminates GH actions. Depletion of MAPK pathway and p70 s6 kinase pathway does not
  • Regulation of GH receptor–JAK2 signaling From: Herrington & Carter-Su (2001)
  • The GH-IGF-Somatic axis
  • THE SULPHATION FACTOR/SOMATOMEDIN/IGF HYPOTHESIS Inject hypophysectomized rat with GH: induces growth and metabolism of cartilage (including incorporation of 35 SO 4 into cartilage) Incubate cartilage from hypox rat with serum from hypox rat + GH - no stimulation of cartilage metabolism Incubate cartilage from hypox rat with serum from GH-treated rat -stimulation of cartilage metabolism SO GH treatment leads to production of a factor in serum which can stimulate cartilage metabolism and growth
  • Insulin-like growth factor I and II IGF I IGF II Somatomedins Non-suppressible-insulin-like-activity (NSILA) Multiplication stimulating activity (MSA)
  • Sequence of IGF II
  • Sequences of insulin and IGFs compared
  • Precursors of insulin and IGFs proinsulin proIGF I proIGF II
  • IGF II Insulin 3D structures of insulin and IGF
  • The GH-IGF-Somatic axis
  • Isaksson
  • The GH-IGF-Somatic axis
  • Endocrine control of mammary gland
  • Mammary gland development
  • Prolactin induces synthesis of the following proteins: Casein Alpha-lactalbumin Lactose synthase Fatty acid synthetase
  • Cytokine signalling From: Shillingford et al (2001)