Essential Endocrinology and Diabetes. Richard I. G. Holt
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Figure 3.7 Growth hormone (GH) signalling and its antagonism. GH binds to its cell‐surface receptors and, via altered conformation of the receptor dimer, recruits Janus‐associated kinase 2 (JAK2). Understanding this model led to the design of the GH receptor antagonist, pegvisomant.
Receptors that recruit tyrosine kinase activity
The family of receptors that bind growth hormone (GH) and prolactin (PRL) also includes those for numerous cytokines and the hormones leptin and erythropoietin (EPO). The basic receptor composition, shown in Figure 3.2, contains major homology between family members in the extracellular domain.
Growth hormone and prolactin signalling pathways – the Janus family of tyrosine kinases
Similar mechanisms govern GH and PRL receptor binding and signal transduction. The hormones are capable of binding two receptors that dimerize. The hormone–dimerized receptor unit induces conformational change in the cytoplasmic regions of the receptor and signal transduction. Discovery of this phenomenon has been utilized in drug design to combat excessive GH action in acromegaly (Figure 3.7; Chapter 5). The EPO receptor also forms homodimers, i.e. two of the same receptors that bind together. In contrast, the cytokine receptors tend to form heterodimers with diverse partner proteins.
Receptor activation by hormone binding rapidly recruits one of four members of the ‘Janus‐associated kinase’ (JAK) family of tyrosine kinases (Figure 3.8), so named after the two‐faced Roman deity, Janus, because of distinctive, tandem kinase domains at their carboxy‐terminals. GH, PRL and EPO receptor dimerization brings together JAK2 molecules that become phosphorylated. The major downstream substrates of JAK are the STAT family of proteins (explaining the term ‘JAK‐STAT’ signalling; Figure 3.8). The name STAT comes from dual function: signal transduction, located in the cytoplasm, and nuclear activation of transcription. Both activities rely on phosphorylation by JAK (Figure 3.8). Phosphorylation causes the STAT proteins to dissociate from the occupied receptor–kinase complex and dimerize themselves, which facilitates access to the nucleus. In the nucleus, dimerized STAT activates target genes, commonly those that regulate proliferation or the differentiation status of the target cell. One of the major targets of GH is the IGF‐I gene (Box 3.5). JAK signalling is not mediated exclusively via STAT. The GH receptor (GHR) also signals through MAPK and PI3‐kinase pathways. This overlap may account for some of the rapid metabolic effects of GH (Figure 3.8).
Defects in the GH signalling pathway can result in rare syndromes of resistance to GH action (Box 3.6 and Figure 3.9).
Figure 3.8 Growth hormone (GH) receptor and its signalling pathways. The receptor recruits tyrosine kinase (TK) activity from Janus‐associated kinase 2 (JAK2). Serum response elements (SREs) are mitogen‐activated protein kinase (MAPK)‐responsive regulatory elements that mediate the induction of target genes, such as c‐fos. STAT, signal transduction and activation of transcription protein; PI3 kinase, phosphatidylinositol‐3‐kinase; IRS, insulin receptor substrate.
Box 3.5 One of the major targets of GH signalling is the IGF‐I gene
Measuring serum IGF‐I is a useful measure of GH activity in the body
G‐protein–coupled receptors
The commonest subset of cell‐surface receptors (>140 members) couples to G‐proteins at the inner surface of the cell membrane. It has been recently discovered by high‐resolution imaging that this receptor‐G‐protein contact occurs at specific hotspots around the cell membrane linked to the cell’s internal cytoskeleton. The contacts last for approximately one second and lead to the generation of intracellular second messengers such as adenosine‐3′,5′‐cyclic monophosphate (cyclic AMP or cAMP), diacylglycerol (DAG) and inositol triphosphate (IP3). In addition to hormones, GPCRs also exist for glutamate, thrombin, odorants and the visual transduction of light.
Box 3.6 Defects in growth hormone signalling pathways and growth hormone resistance syndromes
Severe resistance to GH, mainly secondary to mutations in the GH receptor that commonly affect the hormone‐binding domain, is characterized by grossly impaired growth and is termed Laron syndrome, eponymously named after it was first reported by Laron in 1966 (Figure 3.9).It is an autosomal recessive disorder with a variable phenotype typified by normal or raised circulating GH and low levels of serum IGF‐I.
For other patients, no GHR mutations have been identified, implicating genes that encode downstream components or related aspects of GH signalling.For instance, defects in the IGF‐I gene have been associated with severe intrauterine growth retardation, mild mental retardation, sensorineural deafness and postnatal growth failure.
Figure 3.9 Laron syndrome showing truncal obesity. This boy presented aged 10.4 years but with a height of 95 cm – equivalent to that of a 3‐year‐old. In addition to truncal obesity, there is a very small penis. These features could represent severe growth hormone (GH) deficiency. However, serum GH levels were elevated with undetectable insulin‐like growth factor I (IGF‐I) indicative of GH resistance. Laron syndrome was diagnosed due to an inactivating mutation of the gene encoding the GH receptor. Other clinical features include a prominent forehead, depressed nasal bridge and under‐development of the mandible.
The most striking structural feature of all these receptors is the transmembrane domain comprised of hydrophobic helices, which cross the lipid bilayer of the plasma membrane seven times (