MOLECULAR ENDOCRINOLOGY AND IMMUNOLOGY LECTURE 7 - Mechanism of action of growth hormone and prolactin Growth hormone: general actions; receptor; signal.

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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) signal extracellular transmembrane intracellular Shown to be the real receptor by specificity, and absence in patients with Laron dwarfism

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 IIInsulin 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)