Abstract
BackgroundTNS2 is a focal adhesions protein and a binding partner for many proteins, including the receptor tyrosine kinase Axl. Although TNS2 can bind with Axl, the details of their interactions have not been elucidated. TNS2 is involved in IRS-1 signaling pathway. In this study, we confirmed the relationship between TNS2 expression and the expression of Axl, IRS-1, PDK1 and Glut4 in pancreatic cancer patients.MethodsThe expression levels of TNS2, Axl, IRS-1, PDK1 and Glut4 in human cancer cells were measured by Western blot and/or IP-Western blot assays. Paired samples of pancreatic cancer and non-cancer tissues were obtained from 33 patients and were used to construct tissue microarrays. The expression levels of these markers in the tissue microarrays were measured by enzyme-linked Immunohistochemistry assay, and the relationships were analyzed by Pearson’s chi-square test and two-tailed t-test analysis.ResultsWe demonstrated for the first time that TNS2 is a phosphorylation substrate of Axl. Moreover, we found a positive relationship between TNS2 expression and the expression of Axl, IRS-1, PDK1 and Glut4 in pancreatic cancer patients. Based on these results, we suggest that Axl modulates glucose metabolism potentially through TNS2 and IRS-1. We hypothesize that there exists a novel mechanism whereby Axl binds to and phosphorylates TNS2, releasing TNS2 from interaction with IRS-1 and resulting in increased stability of IRS-1. The two key enzymes of aerobic glycolysis (Glut4 and PDK1) were found to be up-regulated by Axl/TNS2/IRS-1 cross-talk and may play a critical role in glucose metabolism of cancer cells.ConclusionsOur results revealed for the first time that Axl binds to and phosphorylates TNS2 and that Axl/TNS2/IRS-1 cross-talk may potentially play a critical role in glucose metabolism of cancer cells.
Highlights
Tensin 2 (TNS2) is a focal adhesions protein and a binding partner for many proteins, including the receptor tyrosine kinase Axl
When Axl and the Myc-tagged TNS2 expression constructs were co-transfected into Mia PaCa-2 cells, the levels of both TNS2 and p-TNS2 were significantly increased by Axl transfection in a dose-dependent manner (0 to 1.5 μg of Axl plasmid DNA) (Fig. 1c)
(See figure on previous page.) Fig. 3 Axl binds to and phosphorylates TNS2 at tyrosine 483 and regulates cancer cells proliferation. a To demonstrate the binding of TNS2 to Axl, HEK293T cells were transfected with TNS2 or Axl and lysed
Summary
TNS2 is a focal adhesions protein and a binding partner for many proteins, including the receptor tyrosine kinase Axl. TNS2 is involved in IRS-1 signaling pathway. We confirmed the relationship between TNS2 expression and the expression of Axl, IRS-1, PDK1 and Glut in pancreatic cancer patients. Axl is a receptor tyrosine kinase, which is characterized as a pro-oncogenesis factor involved in cancer progression. At high-glucose conditions, Axl binds to and conveys signals through phosphatidylinositol-3-kinase (PI3K), resulting in apoptosis of vascular smooth muscle cells. At low-glucose conditions, Axl binds to the protein tyrosine kinase SHP2;this results in increased cell migration (diabetic cardiovascular disease) and survival (anti-apoptosis) [2]. Whether Axl is involved in cancer metabolism for cancer progression remains largely unknown. For the first time, we demonstrate that Axl may affect glucose metabolism through TNS2
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