Identification of the
            <i>ron</i>
            Gene Product as the Receptor for the Human Macrophage Stimulating Protein

Wang, Ming-Hai; Ronsin, Christophe; Gesnel, Marie-Claude; Coupey, Lionel; Skeel, Alison; Leonard, Edward J.; Breathnach, Richard

doi:10.1126/science.7939629

Cited by 257 publications

(228 citation statements)

References 18 publications

Supporting

Mentioning

225

Contrasting

Unclassified

Order By: Relevance

“…The RON gene encodes a transmembrane tyrosine kinase which has been identi®ed as the receptor for MSP/SF2 (Macrophage Stimulating Protein/Scatter Factor-2, also known as Hepatocyte Growth FactorLike, HGF-L) (Gaudino et al, 1994;Wang et al, 1994). In epithelial cells, Scatter Factors induce a distinctive biological response that involves cytoskeletal reorganization, loss of intercellular junctions and celldissociation, followed by active migration (Gherardi et al, 1989).…”

Section: Introductionmentioning

confidence: 99%

Overexpression of the RON gene in human breast carcinoma

et al. 1998

View full text Add to dashboard Cite

Constitutive activation of the RON gene, known to code for the tyrosine-kinase receptor for Macrophage Stimulating Protein (also known as Scatter Factor 2), has been shown to induce invasive-metastatic phenotype in vitro. As yet, nothing is known about the expression of this novel member of the MET-oncogene family in spontaneously occurring human cancers. Here we report that Ron is expressed at abnormally high levels in about 50% primary breast carcinomas (35/74 patients). Among these, the expression is increased more than 20-fold in 12 cases and the overexpressed protein is constitutively phosphorylated on tyrosine residues. Notably, Ron is only barely detectable in epithelial cells of the mammary gland, and its expression remains unchanged in benign breast lesions (including adenomas and papillomas). Overexpression was observed in di erent histotypic variants of carcinomas; it is associated with the disease at any stage and correlates with the post-menopausal status. In breast carcinoma cells grown in vitro, activation of the Ron receptor resulted in proliferation, migration and invasion through reconstituted basement membranes. Altogether, these data suggest a role for the RON gene in progression of human breast carcinomas to the invasive-metastatic phenotype.

show abstract

Section: Introductionmentioning

confidence: 99%

Overexpression of the RON gene in human breast carcinoma

et al. 1998

View full text Add to dashboard Cite

show abstract

“…Ron is the receptor for MSP (Macrophage Stimulating Protein; Gaudino et al, 1994;Wang et al, 1994). When activated, Ron exerts a wide spectrum of biological activities on target cells of di erent origin: epithelial cells Medico et al, 1996), keratinocytes (Wang et al, 1995), neuroendocrine cells Willett et al, 1997), osteoclasts (Kurihara et al, 1996), and haematopoietic cells Banu et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Point mutations in the tyrosine kinase domain release the oncogenic and metastatic potential of the ron receptor

Santoro¹,

Penengo

Minetto

et al. 1998

Oncogene

View full text Add to dashboard Cite

Ron (the receptor for Macrophage Stimulating Protein) has never been implicated before in human malignancies or in cell transformation. In this report we show that Ron can acquire oncogenic potential by means of two amino acid substitutions ± D1232V and M1254T ± a ecting highly conserved residues in the tyrosine kinase domain. The same mutations in Kit and Ret have been found associated with two human malignancies, mastocytosis and Multiple Endocrine Neoplasia type 2B (MEN2B), respectively. Both mutations caused Ronmediated transformation of 3T3 ®broblasts and tumour formation in nude mice. Moreover, cells transformed by the oncogenic Ron mutants displayed high metastatic potential. The Ron mutant receptors were constitutively active and the catalytic e ciency of the mutated kinase was higher than that of wild-type Ron. Oncogenic Ron mutants enhanced activation of the Ras/MAPK cascade with respect to wild type Ron, without a ecting the JNK/SAPK pathway. Expression of Ron mutants in 3T3 ®broblasts led to di erent patterns of tyrosine-phosphorylated proteins. These data show that point mutations altering catalytic properties and possibly substrate speci®city of the Ron kinase may force cells toward tumorigenesis and metastasis.

show abstract

“…RE7 cells, stably expressing RON as described previously (14), were derived from MDCK cells transfected with wt-RON. The rabbit anti-RON antibody (R5029) was a gift from Prof. Wang (Center for Biology Therapeutics, School of Pharmacy, Texas Tech University Health Sciences Center, USA).…”

Section: Cell Lines and Reagentsmentioning

confidence: 99%

“…Induction of RON phosphorylation and kinase activities can be achieved through ligand-dependent and -independent mechanisms (12). Binding of macrophage stimulating protein (MSP) to extracellular sequences of RON leads to receptor homo-dimerization, which is a typical example of ligand-induced RON activation (13,14). Ligandindependent RON activation was observed in various physiological and pathological conditions (15)(16)(17).…”

Section: Introductionmentioning

confidence: 99%