Anti-apoptotic Signaling by a Colony-stimulating Factor-1 Receptor/Insulin Receptor Chimera with a Juxtamembrane Deletion

• Published in: The Journal of biological chemistry Vol. 273; no. 12; pp. 7169 - 7176
• Main Authors: Boehm, J E, Chaika, O V, Lewis, R E
• Format: Journal Article
• Language: English
• Published: United States American Society for Biochemistry and Molecular Biology 20.03.1998
• Subjects: Animals; Apoptosis; Calcium-Calmodulin-Dependent Protein Kinases - metabolism; Cell Membrane - metabolism; CHO Cells; Cricetinae; DNA Fragmentation; Enzyme Activation; Glucose - metabolism; Macrophage Colony-Stimulating Factor - genetics; Macrophage Colony-Stimulating Factor - metabolism; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; Receptor, Insulin - genetics; Receptor, Insulin - metabolism; Receptor, Macrophage Colony-Stimulating Factor - genetics; Receptor, Macrophage Colony-Stimulating Factor - metabolism; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; Sequence Deletion; Signal Transduction
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.273.12.7169

The intracellular mechanisms used by insulin and insulin-like growth factors to block programmed cell death are unknown. To identify receptor structures and signaling pathways essential for anti-apoptotic effects on cells, we have created a chimeric receptor (colony-stimulating factor-1 receptor/insulin receptor chimera (CSF1R/IR)) connecting the extracellular, ligand-binding domain of the colony-stimulating factor-1 (CSF-1) receptor to the transmembrane and cytoplasmic domains of the insulin receptor. Upon activation with CSF-1, the CSF1R/IR phosphorylates itself and intracellular substrates in a manner characteristic of normal insulin receptors. CSF-1 treatment protected cells expressing the CSF1R/IR from staurosporine-induced apoptosis. A chimeric receptor (CSF1R/IRΔ960) with a deletion of 12 amino acids from its juxtamembrane domain was constructed and expressed. CSF-1-treated cells expressing the CSF1R/IRΔ960 are unable to phosphorylate IRS-1 and Shc (Chaika, O. V., Chaika, N., Volle, D. J., Wilden, P. A., Pirrucello, S. J., and Lewis, R. E. (1997) J. Biol. Chem. 272, 11968–11974). CSF-1 stimulated glucose uptake, mitogen-activated protein kinases, and IRS-1-associated phosphatidylinositol 3′ kinase in cells expressing the CSF1R/IR but not in cells expressing the CSF1R/IRΔ960. Surprisingly, the CSF1R/IRΔ960 was as effective as the CSF1R/IR in mediating CSF-1 protection of cells from staurosporine-induced apoptosis. These observations indicate that the anti-apoptotic effects of the insulin receptor cytoplasmic domain can be mediated by signaling pathways distinct from those requiring IRS-1 and Shc.