cross-phosphorylation, signaling and proliferative functions of the tyro3 and axl receptors in rat2 cellscross-phosphorylation,信号和增殖功能rat2 tyro3和妳受体的细胞.pdfVIP

Cross-Phosphorylation, Signaling and Proliferative Functions of the Tyro3 and Axl Receptors in Rat2 Cells 1,2 1 1 1 1 Jessica E. Brown , Meredith Krodel , Mauricio Pazos , Cary Lai , Anne L. Prieto * 1 Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana, United States of America, 2 Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America Abstract The dysregulation of receptor protein tyrosine kinase (RPTK) function can result in changes in cell proliferation, cell growth and metastasis leading to malignant transformation. Among RPTKs, the TAM receptor family composed of three members Tyro3, Axl, and Mer has been recognized to have a prominent role in cell transformation. In this study we analyzed the consequences of Tyro3 overexpression on cell proliferation, activation of signaling pathways and its functional interactions with Axl. Overexpression of Tyro3 in the Rat2 cell line that expresses Axl, but not Mer or Tyro3, resulted in a 5 fold increase in cell proliferation. This increase was partially blocked by inhibitors of the mitogen-activated protein kinase (MAPK) signaling pathway but not by inhibitors of the phosphatidylinositol 3-kinase (PI(3)K) signaling pathway. Consistent with these findings, an increase in ERK1/2 phosphorylation was detected with Tyro3 but not with Axl overexpression. In contrast, activation of Axl stimulated the PI(3)K pathway, which was mitigated by co-expression of Tyro3. The overexpression of Tyro3 enhanced Gas6-mediated Axl phosphorylation, which was not detected upon overexpression of a ‘‘kinase dead’’ form of Tyro3 (kdTyro3). In addition, the overexpression of Axl induced kdTyr