Читать книгу Handbook of Diabetes - Rudy Bilous - Страница 33

Insulin exerts its main biological effects by binding to a cell surface insulin receptor, a glycoprotein that consists of two extracellular α subunits and two transmembrane β subunits. The receptor has tyrosine kinase enzyme activity (residing in the β subunits), which is stimulated when insulin binds to the receptor. The tyrosine kinase domain phosphorylates tyrosine amino acid residues on various intracellular proteins, such as insulin receptor substrate (IRS)‐1 and IRS‐2, and the β subunit itself (Figure 5.15) (autophosphorylation). The tyrosine kinase activity of the insulin receptor is essential for insulin action.

Post‐receptor downstream signalling events are complex but insulin binding to its receptor leads to phosphorylation of a number of intracellular proteins including IRS‐1 and IRS‐2 (Figure 5.16). Phosphorylated tyrosine residues on these proteins act as docking sites for the non‐covalent binding of proteins with specific ‘SH2’ domains, such as phospatidylinositol 3‐kinase (PI 3‐kinase), Grb2 and phosphotyrosine phosphatase (SHP2). Binding of Grb2 to IRS‐1 initiates a cascade that eventually activates nuclear transcription factors via activation of the proteins Ras and mitogen‐activated protein (MAP) kinase. IRS–PI 3‐kinase binding generates phospholipids that modulate other specific kinases and regulate insulin‐stimulated effects such as glucose transport, and protein and glycogen synthesis.

Figure 5.15 The insulin receptor and its structural domains. Many mutations have been discovered in the insulin receptor, some of which interfere with insulin’s action and can cause insulin resistance; examples are shown in the right column.

Figure 5.16 The insulin signalling cascade. Insulin binding and autophosphorylation of the insulin (and IGF‐1) receptor results in binding of the IRS‐1 protein to the β subunit of the insulin receptor via the IRS phosphotyrosine‐binding domain (PTB). There is then phosphorylation of a number of tyrosine residues (pY) at the C‐terminus of the IRS proteins. This leads to recruitment and binding of downstream signalling proteins, such as PI‐3 kinase, Grb2 and SHP2.