AXL is known to be involved in the later stages of tumor progression such as migration/invasion, metastasis and/or drug resistance. Studies show that TNS2 is a binding partner of many proteins, including the tyrosine kinase Axl, but the details of their interactions have not been elucidated. Tensin 2 is a member of the Tensin family. Here, we demonstrate that TNS2 is a phosphorylation substrate of Axl. We further confirmed the correlationship of TNS2 expression and the expression of Axl, insulin receptor substrat-1 (IRS-1), pyruvate dehydrogenase kinase 1 (PDK1), pyruvate kinase M2 (PKM2) and glucose transporter type 4 (GLUT4) in pancreatic cancer patients. Based on these results, we suggest that Axl may modulate glucose metabolism potentially through TNS2 and IRS-1. We hypothesize that there exists a novel mechanism whereby Axl binds and phosphorylate TNS2 at Y483, releasing TNS2 from interacting with IRS-1 and resulting in increased stability of IRS-1. The three key enzymes of aerobic glycolysis, GLUT4, PDK1 and PKM2, were found to be up-regulated by the Axl/TNS2/IRS-1 cross-talk and may potentially play a critical role in glucose metabolism of cancer cells.
