Insulin receptor-related receptor is expressed in pancreatic beta-cells and stimulates tyrosine phosphorylation of insulin receptor substrate-1 and -2.

Abstract

The receptor-type protein tyrosine kinases in murine pancreatic islets were screened to identify possible growth/differentiation factors in pancreatic beta-cells. The analysis revealed that insulin receptor-related receptor (IRR) is highly expressed in the islets as well as in several highly differentiated beta-cell lines derived from transgenic mice. Islets predominantly contain IRR as uncleaved proreceptors compared with IRR as processed forms in the beta-cell lines, suggesting that the activity of IRR is regulated on the level of processing proteases in vivo. To examine the IRR signaling pathway, a chimeric receptor consisting of the extracellular domain of insulin receptor and the intracellular domain of IRR was expressed in Chinese hamster ovary cells. The hybrid receptor is functional because insulin is capable of tyrosine-phosphorylating the catalytic domain in these cells. It also stimulates the tyrosine phosphorylation of insulin receptor substrate (IRS)-1 and IRS-2, indicating that both proteins serve as substrates of IRR-protein tyrosine kinase in intact cells. The phenotype of the IRS-2 knockout mouse recently reported suggests that an IRS-2-mediated signaling pathway controls the compensatory increase in pancreatic beta-cell mass in insulin-resistant states. From our findings of the specific expression of IRR and its ability of signaling to IRS-2, we speculate that this receptor might play a role in the regulation of beta-cell mass.

Glucose concentration and AMP-dependent kinase activation regulate expression of insulin receptor family members in rat islets and INS-1E beta cells

“…In contrast to IR and IGF-IR, detailed function of IRR that is also strongly regulated by glucose remains unclear. or IGF-IR [19,20]. Nevertheless, until now no morphological or functional abnormalities had been found in islets of IRR knock-out mice and therefore its physiological function in pancreatic beta cells remains unclear [21].…”

“…Also a distinct functional role of hybrid IGF-IRs in mediating their own specific effects has been hypothesised, even if there was no precedence for this [9]. The IRR is an orphan receptor without any known ligand and might predominantly modulate IR or IGF-IR signalling through IRR-IGF-IR or IRR-IR hybrid formation [19,20]. Less is known about IRR and beta cell function, but mutant IRR knock-out mice appear to have normal beta cell mass and beta cell function [21].…”

“…Less is known about IRR and beta cell function, but mutant IRR knock-out mice appear to have normal beta cell mass and beta cell function [21]. Nevertheless, IRR is specifically expressed in pancreatic beta cells and its intracellular tyrosine kinase domain is able to activate insulin receptor substrate (IRS)-1 and IRS-2 [19].…”

Novel Rabphilin-3-like Protein Associates with Insulin-containing Granules in Pancreatic Beta Cells

“…Cell Culture and Tissue Preparation-Pancreatic beta cell lines (␤HC9 and MIN6) and an alpha cell line (␣TC1.6) were cultured in Dulbecco's modified Eagle's medium supplemented with 10% fetal calf serum under 5% CO 2 atmosphere at 37°C as described previously (15). Tissues were immediately excised from 8 -12-week-old C57BL/6J mice killed by cervical dislocation, frozen in a liquid nitrogen bath, and stored at Ϫ80°C.…”

“…Using one of the cDNA fragments preferentially expressed in ␤HC9 cells as a probe (DDBJ/GenBank TM /EBI accession number AB005756), granuphilin cDNAs were cloned from a ␤HC9/MIN6 cell cDNA library (15). Sequencing was performed using an ABI PRISM cycle sequencing kit (Perkin-Elmer).…”