| Description |
Metastasis remains the leading cause of death in breast cancer patients, and the lack of curative treatments accounts for over 40,000 deaths per year. RON receptor tyrosine kinase and short-form RON (sfRON), an N-terminally truncated RON isoform, have emerged as key players in independently promoting breast cancer metastasis through activation of PI3K. As RON and sfRON have been studied individually with respect to metastasis, primary breast tumors concomitantly express both RON and sfRON. However, it is unknown whether a functional interaction exists between RON and sfRON that enhances the tumorigenic or metastatic potential of breast cancer cells. RON inhibitors, targeting the extracellular ligand-binding domain or intracellular kinase domain, are in clinical trials, but there remains a lack of thorough understanding in RON and sfRON biology. Here, through in vitro analysis in the areas of RON and sfRON physical interaction, downstream signaling, cellular localization, internalization, and oncogenic transformation, we have found that RON and sfRON affect each other's phosphorylation in breast cancer cells, independent of detectable physical interaction or significant enhancement of the PI3K/mTORC1/rpS6 signaling axis. Immunofluorescence revealed RON localization at the plasma membrane and cytoplasm, in contrast to the cytoplasmic and perinuclear localization of sfRON in breast cancer cells. The internalization of RON did not appear to be affected by the presence of sfRON, consistent with an apparent inverse expression of RON and sfRON among breast cancer cells. The in vitro analysis suggests redundant roles for RON and sfRON with respect to enhancement of downstream signaling required for metastasis, which juxtaposes their seemingly divergent roles in early breast cancer progression. |
