The differential effects of pp120 (Ceacam 1) on the mitogenic action of insulin and insulin-like growth factor 1 are regulated by the nonconserved tyrosine 1316 in the insulin receptor

Payal Soni, Montaha Lakkis, Matthew N. Poy, Mats A. Fernström, Sonia M. Najjar

Research output: Contribution to journalArticlepeer-review

Abstract

pp120 (Ceacam I) undergoes ligand-stimulated phosphorylation by the insulin receptor, but not by the insulin-like growth factor I receptor (IGF- IR). This differential phosphorylation is regulated by the C terminus of the β-subunit of the insulin receptor, the least conserved domain of the two receptors. In the present studies, deletion and site-directed mutagenesis in stably transfected hepatocytes derived from insulin receptor knockout mice (IR(-/-)) revealed that Tyr(t316), which is replaced by the nonphosphorylatable phenylalanine in IGF-1R, regulated the differential phosphorylation of pp120 by the insulin receptor. Similarly, the nonconserved Tyrt3t6 residue also regulated the differential effect of pp120 on IGF-1 and insulin mitogenesis, with pp120 downregulating the growth-promoting action of insulin, but not that of IGF-1. Thus, it appears that pp120 phosphorylation by the insulin receptor is required and sufficient to mediate its downregulatory effect on the mitogenic action of insulin. Furthermore, the current studies revealed that the C terminus of the β-subunit of the insulin receptor contains elements that suppress the mitogenic action of insulin. Because IR(-/-) hepatocytes are derived from liver, an insulin-targeted tissue, our observations have finally resolved the controversy about the role of the least-conserved domain of insulin and IGF-1Rs in mediating the difference in the mitogenic action of their ligands, with IGF-1 being more mitogenic than insulin.

Original languageEnglish (US)
Pages (from-to)3896-3905
Number of pages10
JournalMolecular and cellular biology
Volume20
Issue number11
DOIs
StatePublished - Jun 2000

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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