Nuclear translocation of RON receptor tyrosine kinase. New mechanistic and functional insights.

Abstract

Receptor tyrosine kinases (RTKs) are membrane sensors that monitor alterations in the extracellular milieu and translate this information into appropriate cellular responses. Epidermal growth factor receptor (EGFR) is the most well-known model in which gene expression is upregulated by mitogenic signals through the activation of multiple signaling cascades or by nuclear translocation of the full-length EGFR protein. RON (Receptuer d'Origine Nantatise, also known as macrophage stimulating 1 receptor, MST1R) has recently gained attention as a therapeutic target for human cancer. This review summarizes the recent understanding of the unusual nuclear translocation of uncleaved RON receptor proteins in response to cellular stresses, such as serum starvation, hormonal deprivation, hypoxia, and genotoxicity. This nonligand mechanism, achieved by RON per se or by interaction with EGFR, may directly activate the transcriptional machinery necessary for cancer cells to survive. In vitro experiments have demonstrated the importance of tyrosine kinase of RON in binding to and activating the c-JUN promoter, HIF-1α, DNA helicase 2, DNA-dependent protein kinase catalytic subunit, and other stress-responsive networks. Nuclear RON-activated nonhomologous end joining repair confers chemoresistance to drugs that induce double-strand breaks (DSBs) in cancer cells. Tyrosine kinase inhibitors or monoclonal antibodies targeting RON kinase may therefore be useful treatments for patients with RON-overexpressing tumors. DSB-inducing anticancer drugs are not recommended for these cancer patients. Moreover, multi-RTK inhibition is a more rational strategy for patients with RON- and RTK-coexpressing human cancer.