Essential Endocrinology and Diabetes. Richard I. G. Holt
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Tyrosine kinase receptors
Phosphorylation of tyrosine kinase receptors can occur through:
tyrosine kinase that is intrinsic to the cytosolic domain of the receptor and activated after hormone–receptor binding; or
separate tyrosine kinases that are recruited to the intracellular portion of the receptor after hormone binding (Figure 3.1).
By either mechanism, the conformational change induced by phosphorylation creates ‘docking’ sites for other proteins. Frequently, this occurs via conserved motifs within the target protein, known as ‘SH2’ or ‘SH3’ domains. These domains may be involved in the activation of downstream kinases or they may stabilize other signalling proteins within a phosphorylation cascade.
Receptors with intrinsic tyrosine kinase activity
Intrinsic tyrosine kinase receptors auto‐phosphorylate upon binding of the appropriate hormone. This group includes the receptors for insulin, epidermal growth factor (EGF), fibroblast growth factor (FGF) and insulin‐like growth factor I ( IGF‐I). EGF and FGF receptors exist as monomers that dimerize upon hormone binding. The dimerization activates tyrosine phosphorylation. Those for insulin and IGF‐I exist in their unoccupied state as preformed dimers. The signalling pathways for all these receptors are heavily involved in cell growth and proliferation.
Insulin signalling pathways
The dimerized insulin receptor comprises two α‐ and two β‐subunits linked by a series of disulphide bridges (Figure 3.6; Chapter 11). When insulin binds, auto‐phosphorylation occurs on the cytosolic domains of the β‐subunit. The activated receptor then phosphorylates two key intermediaries, insulin receptor substrate (IRS) ‐1 or ‐2, which are thought to be essential for almost all the biological actions of insulin. IRS1 has many potential tyrosine phosphorylation sites, at least eight of which are phosphorylated by the activated insulin receptor.
Multiple phosphorylation of IRS‐1 or ‐2 leads to the docking of several proteins with SH2 domains, and the activation of divergent intracellular signalling. For example, docking of phosphatidylinositol‐3‐kinase (PI3‐kinase) leads to deployment of the glucose transporter (GLUT) family members. For instance, in adipose tissue and muscle, GLUT‐4 translocates from intracellular vesicles to the cell membrane, to facilitate glucose uptake into the cell. The mitogenic effects of insulin are mediated via a different intracellular 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).