Loss of PTEN selectively desensitizes upstream IGF1 and insulin signaling

J. Lackey, J. Barnett, L. Davidson, I. H. Batty, N. R. Leslie, C. P. Downes

    Research output: Contribution to journalArticle

    31 Citations (Scopus)

    Abstract

    Many tumors have chronically elevated activity of PI 3-kinase-dependent signaling pathways, caused largely by oncogenic mutation of PI 3-kinase itself or loss of the opposing tumor suppressor lipid phosphatase, PTEN. Several PI 3-kinase-dependent feedback mechanisms have been identified that may affect the sensitivity of upstream receptor signaling, but the events required to initiate an inhibited state have not been addressed. We show that in a variety of cell types, loss of PTEN via experimental knockdown or in tumor cell lines correlates with a block in insulin-like growth factor 1 (IGF1)/insulin signaling, without affecting the sensitivity of platelet-derived growth factor or epidermal growth factor signaling. These effects on IGF/insulin signaling include a reduction of up to five- to tenfold in IGF-stimulated PI 3-kinase activation, a failure to activate the ERK kinases and, in some cells, reduced expression of insulin receptor substrate 1, and both IGF1 and insulin receptors. These data indicate that chronically elevated PI 3-kinase-dependent signaling to the degree seen in many tumors causes a selective loss of sensitivity in IGF1/insulin signaling that could significantly reduce the selective advantage of deregulated activation of IGF1/IGF1-R signaling in tumor development.
    Original languageEnglish
    Pages (from-to)7132-7142
    Number of pages11
    JournalOncogene
    Volume26
    Issue number50
    DOIs
    Publication statusPublished - Nov 2007

    Keywords

    • Phosphatase
    • Signal transduction
    • Insulin-like growth factor
    • Phosphoinositide
    • Tumour suppressor

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  • Cite this

    Lackey, J., Barnett, J., Davidson, L., Batty, I. H., Leslie, N. R., & Downes, C. P. (2007). Loss of PTEN selectively desensitizes upstream IGF1 and insulin signaling. Oncogene, 26(50), 7132-7142. https://doi.org/10.1038/sj.onc.1210520