Lecture 7 (GH

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

intracellular0 247 620

Shown to be the “real” receptor by specificity, and absence in patients with Laron dwarfism

Cytokine receptors

OVINE GH-RECEPTOR HOMOLOGY MODEL

ReceptorReceptor

Intracellular actions

GH-RECEPTOR INTERACTION

JAK Kinases

Soluble tyrosine protein kinases, first named “just another kinase”. Subsequently “janus kinases” (because two apparent binding sites for ATP)

JAK1JAK2JAK3Tyk

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 p70s6 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 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

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:

CaseinAlpha-lactalbuminLactose synthaseFatty acid synthetase

Cytokine signalling

From: Shillingford et al (2001)