Essential Endocrinology and Diabetes. Richard I. G. Holt
pathway. Activated IRS1 docks with the SH2/SH3 domains of the type 2 growth factor receptor‐bound (Grb2) protein. This adaptor protein links IRS1 to the son of sevenless (SoS) protein and, ultimately, to activation of the mitogen‐activated protein kinase (MAPK) pathway, leading to expression of a gene network that promotes mitosis and growth.
Figure 3.5 Intracellular signalling via phosphorylation. (a) Amino acids serine, threonine and tyrosine carry polar hydroxyl (OH) groups that can be phosphorylated. Over 99% of all protein phosphorylation occurs on serine and threonine residues. Phosphorylation of tyrosine, the only amino acid with a phenolic ring, generates particularly distinctive intracellular signalling pathways. (b) Protein 1 is inactive until its hydroxyl group is phosphorylated by the action of a kinase enzyme. This induces a conformational change and an activated phosphorylated protein. Energy for the transfer of the phosphate group comes from the hydrolysis of ATP to ADP. The reverse reaction, from active to inactive states, is catalyzed by a phosphatase and releases inorganic phosphate (Pi) for reincorporation back into ATP. (c) The initiation of a signalling cascade. Activated phosphorylated protein 1 itself acts as a kinase and catalyzes the phosphorylation of protein 2. Amino acid specificity means that serine/threonine kinases usually show no activity with tyrosine residues and tyrosine kinases do not normally phosphorylate serine or threonine residues.
Defects in the insulin signalling pathway can result in resistance to insulin action either as rare monogenic syndromes (Box 3.4) or as a major contributor to type 2 diabetes (Chapters 11 and 13).
Figure 3.6 The insulin receptor and a simplified view of its signalling pathways. The number of insulin receptors on target cells varies, commonly from 100 to 200,000, with adipocytes and hepatocytes expressing the highest numbers. Not all insulin‐signalling pathways are shown, e.g. type 2 growth factor receptor‐bound protein (Grb2) can be stimulated independently of insulin receptor substrate 1 (IRS1). MAPK, mitogen‐activated protein kinase; PI3 kinase, phosphatidylinositol‐3‐kinase; SoS, son of sevenless protein; I, insulin.
Box 3.4 Defects in the insulin signalling pathways and ‘insulin resistance’ syndromes
Over 50 mutations have been reported in the insulin receptor (IR) that impair glucose metabolism and raise serum insulin (‘insulin resistance’).
Historically, insulin receptor mutations have been discovered as different congenital syndromesThe advance of molecular genetics has unified these diagnoses as a phenotypic spectrum according to the severity of IR inactivation.
People with milder insulin resistance and less affected IR signalling are usually only diagnosed at puberty, whereas what was known as ‘Leprachaunism’, with an effective absence of functional IR, manifests as severe intrauterine growth retardation.
People with severe insulin resistance rarely survive beyond the first year of life.
Interestingly, the IR gene is seemingly normal in most people with milder congenital insulin resistance, suggestive of abnormalities in other components of insulin signalling pathways.
Some of these monogenic causes of insulin resistance have now been discovered.
Impaired insulin signalling is also a significant component of type 2 diabetes (Chapters 11 and 13).
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