Insulin receptor /3-subunit cascade

Signal transduction The binding of insulin to the a-subunits of the insulin receptor induces conformational changes that are transduced to the 3-subunits. This promotes a rapid autophosphorylation of a specific tyrosine residue on each 3-subunit (see Figure 23.7). Autophosphorylation initiates a cascade of cellsignaling responses, including phosphorylation of a family of pro teins called insulin receptor substrate (IRS) proteins. At least four... 

Figure 25-14 Mechanism of insulin action. Binding of insulin to the extracellular a-subunit of the insulin receptor induces autophosphorylation of the -subunit of the receptor and phosphorylation of selected intracellular proteins, such as She and the IRS family,These latter phosphoproteins interact with other targets, thereby activating phosphorylation cascades, which result in glucose uptake (in adipose tissue and skeletal muscle), glucose metabolism, synthesis (of glycogen, iipid, and proteins), enhanced gene expression, cell growth, and differentiation, p, protein phosphorylation aPKC, atypical protein kinase C, See text for details.

At the cellular and molecular level, the binding of insulin to a specific membrane spanning receptor initiates a signal transduction cascade which ultimately produces the biological actions of the hormone. The insulin receptor is a tetrameric protein comprised of two a subunits that bind to insulin and two j3 subunits that are linked by disulfide bonds (55,56), and belongs to a subfamily of receptor typrosine kinases which also includes the insulin-like growth factor I (IGF-I) receptor. The a subunits are extracellularly located, while (S subunits span the membrane and have... 

Our consideration of the signal-transduction cascades initiated by epinephrine and insulin included examples of how components of signal-transduction pathways are poised for action, ready to be activated by minor modifications. For example, G-protein a subunits require only the binding of GTP in exchange for GDP to transmit a signal. This exchange reaction is thermodynamically favorable, but it is quite slow in the absence of an appropriate activated 7TM receptor. Similarly, the tyrosine kinase domains of the dimeric insulin receptor are ready for phosphorylation and activation but require the presence of insulin bound between two a subunits to draw the activation loop of one tyrosine kinase into the active site of a partner tyrosine kinase to initiate this process. 

Insulin interacts with its cell surface receptor via key amino acid residues located along the N- and C-termini of the A chain of insulin and along the carboxy terminus of the B chain of insulin (Table 32.6). The binding of insulin occurs to amino acid residues located within the N- and C-terminal regions of the a subunit of the receptor, which includes a cysteine-rich region (5). Binding and activation of the insulin receptor results in a cascade of biochemical events previously described. 

These molecules span the membrane with only one a-helix. The subunits of the dimeric receptor (red and blue) each consist of two polypeptides (a and P) bound by disulfide bonds. The a-chains together bind the insulin, while the p-chains contain the transmembrane helix and, at the C-terminus, domains with tyrosine kinase activity. In the activated state, the kinase domains phosphorylate themselves and also mediator proteins (receptor substrates) that set in motion cascades of further phosphorylations (see pp. 120 and 388). 

---