lecture 11-GH and IGF axis

human growth

• growth is genetically determined

• nutrition, health and growth hormone determine growth

• rate of growth varies with age

• in utero has fastest rate of growth

• rapid period of growth during infancy

• all growth depends on coordinated cellular function

cell behaviour

GH axis

• rise in intracellular cAMP

• liver produces another hormone- IGF-1

• growth hormone has direct and indirect effects

• some IGF-1 produced locally- acts within bone

• IGF-1 has endocrine, paracrine(neighbouring cells) and autocrine(same cell) effects

growth hormone

• gene- part of cluster composed of 5 closely related genes

• GH-N expressed in pituitary gland

• GH-V expressed in placenta(important in pregnancy)

• ancestral gene duplication 3.5×108 years ago

• human GH~75% sequence homology with rat and bovine GH

• GH normally expressed in anterior pituitary

• GH-N gives rise to 22kDa(191 amino acids)-most abundant in plasma 90%, 20kDa(deletion of residues 32-46)

• GH synthesised as precursor protein, N terminal signal peptide cleaved when secreted

• secreted in pulses, more pronounced in males than females

• not sure if shorter version(20kDa) has any specific role

• predominantly produced at night

insulin-like growth factor

• gene on chromosome 12

• 7.5kDa(70 amino acids), significant homology with insulin

• GH and IGF-1 actions

  • promote growth in long bones, soft tissues and organs

  • effects on cellular proliferation, survival, differentiation, metabolism

• can also bind to insulin receptor

• functionally similar to insulin

• good at stimulating cell mitosis

• prevents apoptosis

• affects storage and use

GH and IGF in bones

• growth plate at both ends of long bone

• reserve zone- bone in small clusters in matrix of collagen, progenitor cells

• maturation zone- mature and become chondrocytes secrete matrix

• matrix becomes calcified, acts as scaffold for new bone

GH and IGF in metabolism

• stimulates glycolysis

• stimulates muscle to take up amino acids, converts them into proteins

• hyperglycaemia- increase breakdown of glycogen in liver, increase glucose output, stimulates glucogenesis

• increase glucose uptake into tissue and fat

• growth hormone not involved in normal state

• IGF-1 has opposite actions to growth hormone

GH and IGF-1 act at cell surface receptors

• both are protein hormones

• can’t cross plasma membranes, hydrophilic

• growth hormone receptor has to recruit enzyme

enzyme-coupled receptors

• IGF has enzyme already built it

• intrinsic enzyme is activated

intracellular signalling

• uptake of glucose

• alter amino acid uptake and release

• can have long term effects, alter gene expression

• can have rapid and slow responses

GH and IGF-1 activate kinase cascades

• phosphate added to serine, threonine

• switch signal one

• turn signal off by phosphatase, removes phosphate

GH receptor

• Exists in plasma as homodimer

• Conformational change when gh binds, one subunit rotates, reveals binding site

• Once enzyme recruited, jak2 phosphorylates on residue, cytoplasmic portion, transcription factor

• Stat 5 gets phsophorylated and active, moves into nucleus binds to promoter regions

GH binding protein

• physiological significance of GHBP poorly understood

  • prolong GH half life?

  • compete with GH receptor for GH?

• intracellular portion can be cleaved off

• extracellular portion is GHBP

• role of GHBP is not known

• TNF converting enzyme involved in cleavage of receptor

insulin like growth factor axis

• Heterotetramer- 2 alpha, 2 beta subunits

• Identicalsubunits

• Beta subunits span membrane, alpha are extracellular

• Enzyme already built into beta subunit

  Beta become phosphorylated

• Irs1 becomes phosphorylated, phosphocascade

  Can also phosphorylate ras

• 

• type 2 unknown if it can signal, clearance receptor than signal receptor

insulin-like growth factor axis(ii)

• most IGF present in circulation bound to one IGFBP

• less than 5% IGF free

• BP3 and BP5 have tertiary complex

• others are binary complexes

IGF binding proteins

• majority of IGF associated with IGFBP

  • 6 well characterised

  • evolutionary homology

  • some structural similarities

  • differing regulation and tissue sources

• IGFBP-3 main IGFBP in circulation, storage of IGF

• prolong IGF half life

• transport molecules

• modify IGF action

• IGF levels don’t fluctuate

• long half life, protected from proteolysis

• complex is too big to move out of circulation

• binary complexes are able to leave circulation and can reach target tissue

• can regulate IGF actions

IGF binding proteins regulate IGF activity

• 

• binding proteins have high affinity for IGF

• blocked from acting at receptor

• Igf needs to be released from binding proteins, cleaved by proteases

• Once bp fragmented, binding site, igf can interact with receptor

• Proteolysis, other post translational modification can affect affinity, glycosylation status can affect affinity

• Release igf as appropriate

factors affecting GH and IGF axis

 

Somatostatin can prevent gh secretion

Input from other factors

Prolonged psychological stress

Deep sleep gh increased

Rem gh production less

Ghrelin produced by stomach, potent stimulator for g

hormone deficiency- short stature, adiposity

treatment is to replace IGF

replace with daily injections of GH

hormone excess- gigantism, acromegaly

depends on point in individual’s life

tumour in anterior pituitary

acromegaly has no increase in height, thicker bones

surgery to remove tumour

other hormone regulators of growth

oestrogen involved

levels increase through puberty, lead to apoptosis of cells in reserve zone

nothing to feed into growth plate

thyroid also contribute to long bone, act in hypertrophic zone