Loss of PTEN selectively desensitizes upstream IGF1 and insulin signaling.
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.
Lackey
J
J
Division of Molecular Physiology, School of Life Sciences, University of Dundee, Dundee, Scotland, UK.
Barnett
J
J
Davidson
L
L
Batty
I H
IH
Leslie
N R
NR
Downes
C P
CP
D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D004285:Dogs; D006801:Humans; D007328:Insulin / Q000378:metabolism* / Q000502:physiology; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors / Q000502:physiology*; D051379:Mice; D041681:NIH 3T3 Cells; D051059:PTEN Phosphohydrolase / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000096:biosynthesis / Q000502:physiology; D018129:Phosphatidylinositol Phosphates / Q000096:biosynthesis / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*
D007328:Insulin; D018129:Phosphatidylinositol Phosphates; C060974:phosphatidylinositol 3,4,5-triphosphate; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human