Anti-apoptic signaling by a colony-stimulating factor-1 receptor/insulin receptor chimera with a juxtamembrane deletion

Jason E. Boehm, Oleg V. Chaika, Robert E Lewis

Research output: Contribution to journalArticle

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Abstract

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 expression 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-apoptic effects of the insulin receptor cytoplasmic domain can be mediated by signaling pathways distinct from those requiring IRS-1 and Shc.

Original languageEnglish (US)
Pages (from-to)7169-7176
Number of pages8
JournalJournal of Biological Chemistry
Volume273
Issue number12
DOIs
StatePublished - Mar 20 1998

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Colony-Stimulating Factor Receptors
Macrophage Colony-Stimulating Factor
Insulin Receptor
Staurosporine
Cells
Phosphatidylinositol 3-Kinase
Apoptosis
Cytoprotection
Somatomedins
Cell death
Mitogen-Activated Protein Kinases

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Anti-apoptic signaling by a colony-stimulating factor-1 receptor/insulin receptor chimera with a juxtamembrane deletion. / Boehm, Jason E.; Chaika, Oleg V.; Lewis, Robert E.

In: Journal of Biological Chemistry, Vol. 273, No. 12, 20.03.1998, p. 7169-7176.

Research output: Contribution to journalArticle

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