The insulin receptor (IR) is a tetrameric, tyrosine-kinase receptor, composed of two α-subunits and two transmembrane β-subunits. Alternative splicing of exon 11 generates two structurally different isoforms: IR-A and IR-B. The 12 amino acids derived from exon 11 are included in the IR-B isoform but not in the IR-A isoform. IR-A predominates in tissues with more active proliferation, it is manly expressed in embryonal and fetal tissues, central nervous system (CNS), hematopoietic cells and cancer cells. IR-B is predominantly expressed in adult, well-differentiated tissues, it mediates metabolic insulin actions in liver, muscle and fat. The mechanisms that regulate IR isoform expression are complex and not fully understood. The most relevant functional difference between these two isoforms is the high affinity of IR-A for Insulin-like Growth Factor II (IGF-II), whereas IR-B has a low affinity for IGF-II.
In murine embryonal fibroblasts deprived of Insulin-like Growth Factor I receptor (IGF-IR), IGF-II is able to stimulate cell proliferation through the IR-A isoform. Studies in different breast cancer cells demonstrate that IR-A, the high affinity receptor for IGF-II, promotes cell proliferation. In addition, in various sarcoma cells autocrine IGF-II induces cell invasion and protection from apoptosis via IR-A. These data are confirmed in patients with osteosarcoma, who show elevated serum IGF-II, associated with survival reduction. Both stromal and epithelial cancer cells can locally produce IGF-II, thus suggesting that an autocrine/paracrine IGF-II/IR-A loop promotes cancer cell proliferation.
In agreement with differential roles of insulin receptor isoforms described above, mature human osteoblasts mainly express IR-B, whereas IR-A is more expressed in osteoblast precursors.
Accordingly, insulin receptor isoforms A and B stimulate different intracellular signaling pathways. When activated by insulin, the IR-B mainly generates metabolic effects, whereas the IR-A, activated by insulin or IGF-II, mediates mitogenic effects.