1. IGF and Insulin Receptors
Figure 1 shows the structural features of the receptors for insulin (IR-A and IR-B) and for IGF-1 (IGF-1R) and IGF-2 (IGF-2R). We will first focus on the insulin (blue) and IGF-1 (green) receptors. The genes for IR (22 exons) and IGF-1R (21 exons) are related through a duplication of a 21-exon gene early in vertebrate evolution. Each gene encodes a polypeptide that is processed into the α and β subunits of the receptor. The extracellular domain contains the ligand binding region; there is a single transmembrane segment of 22 or 23 amino acids, and an intracellular tyrosine kinase domain. The IR and IGF-1R share about 50% and 80% homology in the ligand-binding and tyrosine kinase domains, respectively.
Fig1. Receptors for insulin and insulin-like growth factors (IGFs). Each hemireceptor (consisting of one α and one β subunit) is encoded by a separate gene (insulin, blue; IGF-1, green; IGF-2, pink). On the left side of the figure is the B form of the insulin receptor (IR-B; blue; see Chapter 6) which mediates most of the metabolic actions of insulin and does not bind either IGF. Of the 22 exons comprising the gene for the insulin receptor, exon 11, which encodes a 12 amino acid segment at the carboxyl end of the α subunit (purple) of IR-B, is skipped in IR-A. The 21 exon gene for the IGF-1 receptor also lacks this exon. The absence of the 12 amino acids allows these receptors to bind IGF. Above each receptor, including two hybrids, are listed the ligands that bind to it with relatively high affinity (see Table 2). The main consequences of ligand binding to the various receptors are shown in the boxes below the receptors. The receptor for IGF-2 (pink) is a mannose-6-phosphate receptor which binds proteins tagged with this lysosomal breakdown signal. This receptor also binds IGF-2, bringing about its internalization and breakdown.
Table1. Members of the EGF Family
Table2. Ligand Binding by IR-A, IR-B, and IGF-1R
In mammals a small exon, #11, has been incorporated into the gene for the IR. This exon encodes a twelve amino acid sequence that occurs at the carboxyl terminus of the α subunit (purple segment in Figure 1), the presence of which prohibits the binding of both IGFs. This exon can be and is skipped, on a cell-specific basis, during the processing of the mRNA for IR, generating IR-A which lacks the amino acids encoded by exon 11 and binds both insulin and IGF-2. This renders mammalian cells capable of responding only or primarily to the metabolic effects of insulin (IR-B) or to the growth promoting effects one of the IGFs (IR-A). For example, the liver, skeletal muscle, and adipose tissue contain 80%, 60%, and 60%, respectively, IR-B, which binds only insulin. These tissues, along with the kidney are the pre dominant sites of IR-B expression in the adult, whereas IR-A is ubiquitous. IR-A is also the major form expressed in fetal tissues and in certain cancerous tissues.
Some cells and tissues exhibit hybrid receptors as shown in Figure 1. The ability of the various receptor forms to bind insulin, IGF-1, or IGF2 are also depicted. A semiquantitative comparison of these affinities is presented in Table 1.
The receptor for IGF-2 (IGF-2R) is also known as a cation-independent mannose-6-phosphate receptor. In addition to binding extracellular IGF-2, it binds man nose-6- phosphate-tagged proteins in the trans-golgi network that are destined for lysosomal breakdown. Bound IGF-2 is also transported to lysosomes. Thus the function of this protein, in the context of the IGFs, is to remove IGF-2 from the pericellular environment and thus attenuate its intracellular signaling potential through IR-A or IGF-1R. The binding site on IGF-2 for the IGF-2R is different from the one used to bind the IR-A and IGF-1 receptors.
The bottom portion of Figure 1 depicts the bio logical consequences of activating the different receptor forms. IR-B mediates the metabolic effects of insulin; the IGF-2R mediates the removal of its ligand. The remaining receptors, in the central portion of the figure, bring about, depending on cell context, changes in pathways that lead to the cell’s growth and survival.
2. IR and IGF-R Signaling
The signaling pathways utilized by the activated IRs and IGF-1R begin in the typical way for RTK receptors with autophosphorylation of the cytoplasmic portion of the receptor and recruitment of effector and adaptor proteins such as IRS-1 (insulin receptor substrate). These provide docking sites SH2 (Scr Homology 2) effector proteins such as the regulatory p85 subunit of PI3 kinase or the adaptor protein GRB2. These events lead to the activation of the PI3 kinase pathway or the Ras-mediated activation of the MAP kinase pathway. Evidence has accumulated that the predominant pathway and its physiological outcome depend on: (i) the receptor initiating the pathway, i.e., IR-B, IR-A; or IGF-1R.; (ii) The ligand binding to the receptor, especially whether insulin or IGF-2 is the ligand for IR-B; and the cell context, particularly other mitogenic signals the cell is subject to. It is this variability in the precise signaling pathways used that leads to the different constellation of physiological outcomes depicted at the bottom of Figure 1.
