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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.

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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

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signal

transmembrane

0

247

620

extracellular

intracellular

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

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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

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GH Receptor and jak2

From: Herrington & Carter-Su (2001)

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GH signalling

From: Herrington & Carter-Su (2001)

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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 p70s6 kinase pathway does not

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Regulation of GH receptor–JAK2 signaling

From: Herrington & Carter-Su (2001)

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THE SULPHATION FACTOR/SOMATOMEDIN/IGF HYPOTHESIS

Inject hypophysectomized rat with GH: induces growth and metabolism of cartilage (including incorporation of 35SO4 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

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Insulin-like growth factor I and II

IGF I IGF II

Somatomedins

Non-suppressible-insulin-like-activity (NSILA)

Multiplication stimulating activity (MSA)

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Precursors of insulin and IGFs

proinsulin

proIGF I

proIGF II

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Prolactin induces synthesis of the following proteins:

Casein

Alpha-lactalbumin

Lactose synthase

Fatty acid synthetase

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Cytokine signalling

From: Shillingford et al (2001)