The role of the insulin receptor substrate-1 in the differentiation of rat hippocampal neuronal cells

A. Morrione, M. Navarro, G. Romano, M. Dews, K. Reiss, B. Valentinis, B. Belletti, R. Baserga

Research output: Contribution to journalArticlepeer-review

Abstract

H19-7/IGF-IR cells are rat hippocampal cells expressing a human IGF-I receptor, which differentiate to a neuronal phenotype when stimulated by IGF-I at 39°C. H19-7/IGF-IR cells have low levels of expression of insulin receptor substrate-1 (IRS-1), a major substrate of the IGF-IR. IGF-I induces serine-phosphorylation and down-regulation of the endogenous IRS-1 upon differentiation of H19-7/IGF-IR cells. The profound influence of IRS-1 on differentiation of H19-7/IGF-IR cells was confirmed by transfecting these cells with a plasmid expressing mouse IRS-1. Over-expression of wild type IRS-1 in H19-7/IGF-IR cells abolishes IGF-I-induced differentiation at 39°C. A mutant of IRS-1 lacking the PTB domain loses the ability to inhibit the differentiation program. H19-7/IGF-IR/IRS-1 cells at 39°C show a stronger and prolonged activation of Akt, when compared to H19-7/IGF-IR cells. The role of Akt in the inhibition of the differentiation program was confirmed by using the inhibitor of Class I PI3 kinases LY29400, which restores IGF-I-induced differentiation of H19-7/IGF-IR/IRS-1 cells. H19-7/IGF-IR/IRS-1 cells show a strong reduction in MAP kinases signaling, which is related to the superactivation of Akt. This was confirmed by expressing in H19-7/IGF-IR cells a constitutively active Akt, which inhibited MAP kinases activation in these cells. These experiments confirm the importance of MAPK in the mechanism of IGF-I-mediated differentiation of H19-7/IGF-IR cells.

Original languageEnglish
Pages (from-to)4842-4852
Number of pages11
JournalOncogene
Volume20
Issue number35
DOIs
Publication statusPublished - Aug 9 2001

Keywords

  • IGF-I, insulin-like growth factor-I
  • IGF-II, insulin-like growth factor-II
  • IGF-IR, insulin-like growth factor-1 receptor
  • IRS-1, insulin receptor substrate-1
  • PI3K, phosphatidylinositol-3 kinase

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Fingerprint

Dive into the research topics of 'The role of the insulin receptor substrate-1 in the differentiation of rat hippocampal neuronal cells'. Together they form a unique fingerprint.

Cite this