Point mutations and overexpression of Ron induce transformation, tumor formation, and metastasis

Abstract

The receptor tyrosine kinase Ron is a member of the receptor family that includes the proto-oncogene Met and the avian oncogene Sea. The interaction of Ron with its ligand, known as hepatocyte growth factor-like protein (HGFL) or macrophage stimulating protein (MSP), induces crucial cellular responses including invasive growth, proliferation, cell scattering, and branching morphogenesis. Based on the homology and functional similarities between Met and Ron it was hypothesized that Ron may be important in tumor formation and metastasis. To test this hypothesis, wildtype mouse Ron and three mutant forms of Ron containing mutations similar to those found in the Met gene in human hereditary papillary renal carcinoma (HPRC), were expressed in NIH3T3 cells. A transformed phenotype was produced in cell lines expressing either wild-type Ron or the mutated Ron proteins. Further, these cell lines displayed oncogenic potential by exhibiting increased proliferation and constitutive phosphorylation of Ron. These cell lines were also tested for the ability to form solid tumors. Cells expressing wild-type Ron and the three proteins with single amino acid substitutions were highly tumorigenic in vivo. In a model of experimental metastasis, two of the cell lines with altered Ron protein formed highly aggressive tumors in the lungs. These results suggest that Ron may be an aggressive oncogene when either overexpressed or when activated by mutation. Oncogene (2001) 20, 6142 ± 6151.

Sf-Stk kinase activity and the Grb2 binding site are required for Epo-independent growth of primary erythroblasts infected with Friend virus

“…Since the glycine at position 308 diverges from the conserved aspartic acid residue found in most receptor tyrosine kinases, we sequenced the Stk kinase domain from multiple mouse strains and observed a glycine at this position in each instance, ruling out the possibility that a mutation was introduced during the cloning of Stk or that this glycine represents a polymorphism in the murine Stk locus. Interestingly, expression of Stk has recently been shown to be transforming in NIH3T3 cells (Peace et al, 2001), whereas expression of human RON, which has the conserved aspartic acid at this position, fails to transform these cells (Santoro et al, 1998). Thus, the presence of a glycine residue at position 308 appears to be murine-speci®c, and may be exploited by Friend virus to aid in the expansion of infected cells.…”

Altered expression of the RON receptor tyrosine kinase in primary human colorectal adenocarcinomas: generation of different splicing RON variants and their oncogenic potential

“…To our knowledge, this is the first naturally occurring human RON variants that have cell-transforming and tumor-growth activities. In contrast, mouse wtRON, also known as STK (Iwama et al, 1994), has the ability to induce tumor formation in vivo (Peace et al, 2001). Human wtRON or ROND165 has never showed cell transformation and tumor-formation activities Santoro et al, 1996Santoro et al, , 1998Williams et al, 1999), instead, it induces the motile-invasive phenotypes Santoro et al, 1996).…”

“…In vivo tumorigenesis and metastasis assays These assays were performed as previously described (Santoro et al, 1998;Peace et al, 2001). Briefly, pooled NIH3T3 cells transfected with pcDNA3.1 vector alone or with cDNA encoding wtRON, RON-M1254T, ROND160, and ROND155, respectively, were harvested from culture dishes and suspended in 0.2 ml serum-free DMEM prior to injection.…”

RON(MST1R)is a novel prognostic marker and therapeutic target for gastroesophageal adenocarcinoma

“…18 Immunohistochemistry (IHC) of various tumor types revealed RON overexpression, including GEC. 19,20 RON mediates oncogenic phenotypes in lung, thyroid, pancreas, prostate, colon and breast cancer cells [21][22][23][24][25][26][27][28][29] and predicts a poor prognosis in human breast cancer. 30 RON promotes similar, but not identical, MSP-independent and MSP-dependent phenotypes in breast cancer cells.…”