Oncogenic and invasive potentials of human macrophage-stimulating protein receptor, the RON receptor tyrosine kinase

Abstract

The product of the RON (recepteur d'origine nantais) gene belongs to the MET proto-oncogene family, a distinct subfamily of receptor tyrosine kinases. The ligand of RON was identified as macrophage-stimulating protein (MSP), a member of the plasminogen-related growth factor family. RON is mainly expressed in cells of epithelial origin and is required for embryonic development. In vitro RON activation results in epithelial cell dissociation, migration and matrix invasion, suggesting that RON might be involved in the pathogenesis of certain epithelial cancers in vivo. Indeed, recent studies have shown that RON expression is significantly altered in several primary human cancers, including those of the breast and colon. Truncation of the RON protein has also been found in primary tumors from the gastrointestinal tract. These alterations lead to constitutive activation of RON that causes cell transformation in vitro, induces neoplasm formation in athymic nude mice, and promotes tumor metastasis into the lung. Studies employing transgenic models further demonstrated that over-expression of RON in lung epithelial cells results in multiple tumor formation with features of large cell undifferentiated carcinoma. The oncogenic activities of RON are mediated by RON-transduced signals that promote unbalanced cell growth and transformation leading to tumor development. Thus, abnormal accumulation and activation of RON could play a critical role in vivo in the progression of certain malignant human epithelial cancers.

Small interfering RNA-directed targeting of RON alters invasive and oncogenic phenotypes of human hepatocellular carcinoma cells

“…RON modulates diverse processes involved in tumor progression and metastasis in a variety of human cancers (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27). Consequently, an understanding of the molecular alterations of RON that facilitate tumor progression and metastasis will provide insight into approaches to optimized target therapies.…”

“…Amplification and/or overexpression of RON transduces oncogenic signals that regulate tumorigenic activities of a majority of cancer cell lines examined (13)(14)(15)(16)(17)(18)(19). Akt is a serine/ threonine protein kinase and involved in a wide variety of cellular functions including cellular proliferation, survival and differentiation.…”

“…The recepteur d'origine nantais (RON) has features of a classical receptor tyrosine kinase and belongs to the MET proto-oncogene family. RON is a heterodimeric protein of disulfide-linked extracellular α and transmembrane β subunits with intrinsic tyrosine kinase activity derived from proteolytic cleavage of a single-chain precursor of 170 kDa (13)(14)(15)(16)(17)(18)(19). Transgenic mouse models overexpressing RON in lung or mammary epithelial cells develop lung and breast carcinomas and are associated with metastatic dissemination (20,21).…”

“…Activation of the RON is essential in transducing a variety of intracellular signaling cascades including the phosphatidylinositol-3 kinase (PI3K)/Akt, mitogen-activated protein kinase (MAPK) including extracellular signal-regulated kinase (ERK), β-catenin and nuclear factor-κB (NF-κB) that lead to cellular growth, motility and invasion of extracellular matrices (13)(14)(15)(16)(17)(18)(19).…”

MET and MST1R as prognostic factors for classical Hodgkin's lymphoma

“…19,20,25 MST1R (RON), an RTK with homology to MET, is involved in tumor progression and metastasis. 26,27 MST1R is overexpressed in human epithelial malignancies. 28,29 The expressions of MET and MST1R have been detected in HRS cells in patients with cHL.…”