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Signaling Differences from the A and B Isoforms of the Insulin Receptor (IR) in 32D Cells in the Presence or Absence of IR Substrate-1

Dipartimento di Medicina Interna e Medicina Specialistica (L.S., R.V.), University of Catania, Ospedale Garibaldi, 95123 Catania, Italy; Kimmel Cancer Center (M.P., A.W., R.B.), Thomas Jefferson University, Philadelphia, Pennsylvania 19107; Dipartimento di Medicina Clinica e Sperimentale (A.B.), Cattedra di Endocrinologia, University of Catanzaro, Policlinico Mater Domini, 88100 Catanzaro, Italy

Address all correspondence and requests for reprints to: Renato Baserga, M.D., Kimmel Cancer Center, Thomas Jefferson University, 233 South 10th Street, 624 Bluemle Life Sciences Building, Philadelphia, Pennsylvania 19107.

The A isoform of the insulin receptor (IR) is frequently overexpressed in cancer cells and is activated by IGF-II as well as by insulin, whereas the B isoform is predominant in differentiated tissues and responds poorly to IGF-II. The IR substrate-1 (IRS-1), a docking protein for the IR, is known to send a mitogenic signal and to be a powerful inhibitor of cell differentiation. We have investigated the biological effects of the two IR isoforms in parental 32D hemopoietic cells, which do not express IRS-1, and in 32D-derived cells in which IRS-1 is ectopically expressed. The effects of the two isoforms on cell survival, differentiation markers and nuclear translocation of IRS-1 were compared. The results confirm that the A isoform responds to IGF-II and preferentially sends mitogenic, antiapoptotic signals, whereas the B form, poorly responsive to IGF-II, tends to send differentiation signals.

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