Original Article

Oncogene (2007) 26, 7132–7142; doi:10.1038/sj.onc.1210520; published online 7 May 2007

Loss of PTEN selectively desensitizes upstream IGF1 and insulin signaling

J Lackey1,2, J Barnett1,2, L Davidson1, I H Batty1, N R Leslie1 and C P Downes1

1Division of Molecular Physiology, School of Life Sciences, University of Dundee, Dundee, Scotland, UK

Correspondence: Dr NR Leslie, Division of Molecular Physiology, College of Life Sciences, University of Dundee, Dow Street, Dundee, Scotland DD1 5EH, UK. E-mail: n.r.leslie@dundee.ac.uk

2These authors have contributed equally to this study.

Received 12 December 2006; Revised 29 March 2007; Accepted 2 April 2007; Published online 7 May 2007.

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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.

Keywords:

phosphatase, signal transduction, feedback, insulin-like growth factor, phosphoinositide, tumor suppressor

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