Ron-receptor tyrosine kinase in tumorigenesis and metastasis.
ABSTRACT The Ron-receptor tyrosine kinase has been increasingly recognized for its tumorigenic potential in the last decade. Ron-receptor activation leads to the activation of common receptor tyrosine kinase downstream-signaling pathways, and most prominently in tumor models, activation of MAPK, PI3K and beta-catenin. Numerous experimental models of mammalian tumorigenesis have demonstrated that increased Ron-receptor activity correlates with increased tumorigenesis in a variety of organs of epithelial origin. The evidence for Ron as an oncogene in human tumor biology is growing. The Ron receptor is overexpressed and over activated in a large number of human tumors, and overexpression of Ron correlates with a worse clinical outcome for patients in at least two human cancer states, namely breast and bladder cancer. Several experimental approaches have been demonstrated to successfully block Ron activity and function, and given these convincing data, approaches to block Ron-receptor activity in targeted human cancers should prove to be fruitful in the setting of future clinical research trials.
- SourceAvailable from: jbc.org[show abstract] [hide abstract]
ABSTRACT: Human serum macrophage stimulating protein (MSP) is a disulfide-linked heterodimer that induces motile and phagocytic activity of mouse resident peritoneal macrophages. It is a member of the family of kringle proteins, which typically exist in extracellular fluid as single chain precursors that are activated by proteolytic cleavage. In this work, we expressed [35S]cysteine-labeled recombinant pro-MSP in MSP cDNA-transfected Chinese hamster ovary cells and studied proteolytic processing of pro-MSP and the requirement of cleavage for biological activity. In media containing heat-inactivated fetal bovine serum, the protein was secreted as single chain pro-MSP, which was cleaved over a period of hours to the mature heterodimer. Cleavage was prevented by serine protease inhibitors such as leupeptin or aprotinin; it did not occur if cells were cultured in serum-free medium. Nanomolar concentrations of coagulation proteases kallikrein, factor XIIa or factor XIa cleaved pro-MSP to MSP within 30 min. Pro-MSP had no biological activity. After cleavage by kallikrein, biological activity was quantitatively comparable to that of natural MSP isolated from human plasma. These results support our hypothesis that MSP circulates as the biologically inactive precursor and can be activated by enzymes of the intrinsic coagulation cascade.Journal of Biological Chemistry 03/1994; 269(5):3436-40. · 4.65 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: The formation of stable cell-cell adhesions by type I cadherins depends on the association of their cytoplasmic domain with beta-catenin, and of beta-catenin with alpha-catenin. The binding of beta-catenin to these partners is regulated by phosphorylation of at least three critical tyrosine residues. Each of these residues is targeted by one or more specific kinases: Y142 by Fyn, Fer and cMet; Y489 by Abl; and Y654 by Src and the epidermal growth factor receptor. Developmental and physiological signals have been identified that initiate the specific phosphorylation and dephosphorylation of these residues, regulating cadherin function during neurite outgrowth, permeability of airway epithelium and synapse remodeling, and possibly initiating epithelial cell migration during development and metastasis.Current Opinion in Cell Biology 11/2005; 17(5):459-65. · 11.41 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: The RON receptor tyrosine kinase is a member of the MET proto-oncogene family that has been implicated in regulating motile-invasive phenotypes in certain types of epithelial cancers. The purpose of this study was to determine if RON expression is altered in primary human colorectal adenocarcinomas. Results from immunohistochemical staining showed that RON is highly expressed in the majority of colorectal adenocarcinomas (29/49 cases). Accumulated RON is also constitutively active with autophosphorylation in tyrosine residues. Moreover, three splicing variants of RON, namely RONdelta165, RONdelta160, and RONdelta155 were detected and cloned from two primary colon cancer samples. These RON variants were generated by deletions in different regions in extracellular domains of the RON beta chain. Functional studies showed that expression of RONdelta160 or RONdelta155 in Martin-Darby canine kidney cells resulted in increased cell dissociation (scatter-like activity). RON variants, RONdelta160 and RONdelta155, also exerted the ability to induce multiple focus formation and sustain anchorage-independent growth of transfected NIH3T3 cells. Moreover, NIH3T3 cells expressing RONdelta160 or RONdelta155 formed tumors in athymic nude mice and colonized in the lungs. These data suggest that RON expression is altered in certain primary colon cancers. Abnormal accumulation of RON variants may play a role in the progression of certain colorectal cancers in vivo.Oncogene 02/2003; 22(2):186-97. · 7.36 Impact Factor