A Twenty-First Century Cancer Epidemic Caused by Obesity: The Involvement of Insulin, Diabetes, and Insulin-Like Growth Factors
Figure 6
Representation of the domain structure of the human insulin and type I IGF receptors. The insulin receptor and type I IGF receptor are synthesised as single polypeptide chains that comprise several congruent, distinct domains. A linear representation of the domain structure of the proinsulin receptor isoform B after the removal of the signal peptide is shown above, a representation of the homodimer (a). From the amino-terminus, the individual domains are coloured as follows: leucine-rich repeat domain 1 (L1, blue), a cysteine-rich region (CR, yellow), a second leucine-rich repeat domain (L2, blue) followed by three fibronectin type III domains (FnIII-1, FnIII-2, and FnIII-3, different shades of pale blue). FnIII-2 is interrupted by a ~120 residue insert domain (ID, grey) that contains the furin proteolytic cleavage site which is cleaved by a protease to create the α and β chains of the receptors. The segments of the insert domain that are in the α and β chains are termed IDα and IDβ, respectively. The single helix that spans the plasma membrane (TM, dashed line) is C-terminal to the FnIII-3 domain and is followed by the intracellular domains comprising a ~40 amino acid residue intracellular juxtamembrane region (JM, dashed line), a tyrosine kinase (TK) catalytic domain, and an ~60 amino acid residue carboxyl-terminal tail. Intramonomer and intermonomer disulphide bonds are shown as ochre coloured connecting lines. The position of the furin cleavage site is indicated below the proinsulin receptor monomer and the position of the extra 12 amino acid residues present in isoform B of the insulin receptor is indicated below the depiction of the mature insulin receptor dimer. The amino acid sequences around the furin cleavage sites in isoform A and isoform B [311] of the insulin receptors are shown (b). The additional 12 residues encoded by exon 11 that are present in isoform B of the insulin receptor are shown in bold. The presence of 12 additional residues, three amino acids from the carboxy-terminus of the α-chain, in the α-chain insert domain impinges upon Site 1 of the insulin receptor binding pocket [84] and affects the ability of IGF-1 and IGF-2 to interact with the insulin receptor isoform B.
