Insulin Receptor Substrate Is a Mediator of Phosphoinositide 3-Kinase Activation in Quiescent Pancreatic Cancer Cells
Open Access
- 15 October 2005
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 65 (20) , 9164-9168
- https://doi.org/10.1158/0008-5472.can-05-0779
Abstract
Phosphoinositide 3-kinase (PI3K) is activated in pancreatic cancer cells and plays a central role in their proliferation, survival, and drug resistance. Although the mechanism is unclear, PI3K activation in these cells could be due to physical interaction between its regulatory subunit (p85) and specific tyrosine kinases or their mediators. Consistent with this possibility, PI3K was precipitated with anti-phosphotyrosine antibodies and Akt phosphorylation was blocked by the tyrosine kinase inhibitors SU6656 and PD158780 in quiescent pancreatic cancer cells. Pull-down assays with a fusion protein (GST-p85NC-SH2), and coimmunoprecipitation studies, indicated that the insulin receptor substrate (IRS), and not the epidermal growth factor and insulin-like growth factor receptors or the Src tyrosine kinase, was physically associated with PI3K in these cells. Our data also indicated that SU6656 and PD158780 inhibited Akt activation in pancreatic cancer cells by interfering with the ability of IRS-1 to recruit PI3K. Furthermore, IRS-1 was phosphorylated on a p85-binding site (Y612), and IRS-specific small interfering RNA potently inhibited activation of PI3K and Akt in transfected cells. Taken together, these observations indicate that IRS is a mediator of PI3K activation in quiescent pancreatic cancer cells.Keywords
This publication has 21 references indexed in Scilit:
- The PI 3-kinase/Akt signaling pathway is activated due to aberrant Pten expression and targets transcription factors NF-κB and c-Myc in pancreatic cancer cellsOncogene, 2004
- Reciprocal feedback regulation of insulin receptor and insulin receptor substrate tyrosine phosphorylation by phosphoinositide 3-kinase in primary adipocytesBiochemical Journal, 2002
- Epidermal Growth Factor and Transforming Growth Factor α Mimic the Effects of Insulin in Human Fat Cells and Augment Downstream Signaling in Insulin ResistanceJournal of Biological Chemistry, 2002
- The phosphatidylinositol 3-Kinase–AKT pathway in human cancerNature Reviews Cancer, 2002
- Aberrant expression and activation of insulin-like growth factor-1 receptor (IGF-1R) are mediated by an induction of IGF-1R promoter activity and stabilization of IGF-1R mRNA and contributes to growth factor independence and increased survival of the pancreatic cancer cell line MIA PaCa-2Oncogene, 2001
- Tumor Suppressor MMAC/PTEN Inhibits Cytokine-induced NFκB Activation without Interfering with the IκB Degradation PathwayPublished by Elsevier ,2001
- Tyrosine Kinase Inhibitors. 14. Structure−Activity Relationships for Methyl- amino-Substituted Derivatives of 4-[(3-Bromophenyl)amino]-6-(methylamino)- pyrido[3,4-d]pyrimidine (PD 158780), a Potent and Specific Inhibitor of the Tyrosine Kinase Activity of Receptors for the EGF Family of Growth FactorsJournal of Medicinal Chemistry, 1998
- The IRS‐signalling system during insulin and cytokine actionBioEssays, 1997
- Increased Expression of Insulin Receptor Substrate-1 in Human Pancreatic CancerBiochemical and Biophysical Research Communications, 1996
- Structure, regulation and function of phosphoinositide 3-kinasesBiochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 1994