Presence of RON receptor tyrosine kinase and its splicing variant in malignant and non-malignant human colonic mucosa.

Okino, Tetsuya; Egami, Hiroshi; Ohmachi, H; Takai, Eiji; Tamori, Yasuhiro; Nakagawa, Kazuhiro; Nakano, Satoshi; Akagi, Junji; Sakamoto, Osamu; Suda, Toshio; Ogawa, Michio

doi:10.3892/ijo.15.4.709

Cited by 18 publications

(24 citation statements)

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“…In colorectal cancers, increased RON expression is accompanied with the generation of oncogenic variant RON160 and RON155 and results in increased motile-invasive phenotypes (20,27). Similar effects are also seen in breast tumors, in which RON165 expression promotes aggressive behavior of cancerous cells (14,16).…”

Section: Discussionsupporting

confidence: 50%

“…1A and our survey of primary BC samples and BC cell lines, the complete deletion of exon 11 is readily detected in the majority of tumor samples and cell lines. Analysis of published articles also reveals that the complete deletion of exon 11 commonly occurs not only in tumor samples, but also in normal epithelial cells such as cell of colonic mucosa (14,27). However, the synthesis of the RON165 protein occurs mainly in cancerous samples but not in normal epithelial cells (14,27).…”

Section: Discussionmentioning

confidence: 99%

“…Analysis of published articles also reveals that the complete deletion of exon 11 commonly occurs not only in tumor samples, but also in normal epithelial cells such as cell of colonic mucosa (14,27). However, the synthesis of the RON165 protein occurs mainly in cancerous samples but not in normal epithelial cells (14,27). The inability of normal epithelial cells to produce RON165 even in the presence of naturally occurring RON165 mRNA transcript seems to be a mechanism responsible for maintaining the integrity of the normal epithelial layer.…”

Section: Discussionmentioning

confidence: 99%

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Alterations in a defined extracellular region of the RON receptor tyrosine kinase promote RON-mediated motile and invasive phenotypes in epithelial cells

Zhang

Zhou²,

Yao³

et al. 2009

Int J Oncol

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Abstract. Cell migration followed by matrix invasion is a critical step required for epithelial cell differentiation, growth and survival. This study determined the RON receptor in regulation of motile-invasive phenotypes of epithelial cells. Two RON variants, RON165.e11p and RON165, with alterations in a defined extracellular domain were used as the model. RON165 is a splicing variant generated by an mRNA transcript with an in-frame deletion of 49 amino acids encoded by exon 11. In contrast, RON165.e11p was produced by a partial deletion of exon 11 with the elimination of the first 40 amino acids. Thus, RON165.e11p differs from RON165 with nine amino acids retained in the fourth immunoglobulin-plexin-transcription (IPT) domain. Biochemically, both RON165 and RON165.e11p exist as a single-chain protein, residing in the cytoplasm, and failed to mature into the two-chain receptor. Both RON165 and RON165.e11p spontaneously formed oligomers in vivo leading to constitutive phosphorylation and the activation of downstream signaling proteins. Although lacking celltransforming activities, RON165 and RON165.e11p mediated the epithelial to mesenchymal transition with spindle-like cell morphologies, diminished E-cadherin expression, and increased N-cadherin and vimentin expression. These changes facilitated epithelial cell migration and invasion as modeled in Martin-Darby canine kidney (MDCK) cells. Moreover, expression of RON165 or RON165.e11p in breast epithelial MCF-7 cells diminished epithelial cell phenotypes and increased motile and invasive activities. Thus, alterations in the defined extracellular region result in two unique RON variants with similar biological properties. The ability of RON165 or RON165.e11p to promote motile-invasive phenotypes may represent a mechanism by which RON regulates epithelial cell phenotypes and biological activities.

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Section: Discussionsupporting

confidence: 50%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Alterations in a defined extracellular region of the RON receptor tyrosine kinase promote RON-mediated motile and invasive phenotypes in epithelial cells

Zhang

Zhou²,

Yao³

et al. 2009

Int J Oncol

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“…Constitutively active splice variants of Ron have also been identified in human colon cancer cell lines and tissues (34)(35)(36), making Ron an obvious target for further understanding aggressive disease. Therefore, we produced and characterized various transgenic lines that overexpress either the WT form of Ron or a constitutively active form of Ron within the mammary gland to assess and better understand the biology behind Ron overexpression.…”

Section: Discussionmentioning

confidence: 99%

Mammary-Specific Ron Receptor Overexpression Induces Highly Metastatic Mammary Tumors Associated with β-Catenin Activation

Zinser¹,

Leonis

Toney³

et al. 2006

Cancer Research

104

151

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Activated growth factor receptor tyrosine kinases (RTK) play pivotal roles in a variety of human cancers, including breast cancer. Ron, a member of the Met RTK proto-oncogene family, is overexpressed or constitutively active in 50% of human breast cancers. To define the significance of Ron overexpression and activation in vivo, we generated transgenic mice that overexpress a wild-type or constitutively active Ron receptor in the mammary epithelium. In these animals, Ron expression is significantly elevated in mammary glands and leads to a hyperplastic phenotype by 12 weeks of age. Ron overexpression is sufficient to induce mammary transformation in all transgenic animals and is associated with a high degree of metastasis, with metastatic foci detected in liver and lungs of >86% of all transgenic animals. Furthermore, we show that Ron overexpression leads to receptor phosphorylation and is associated with elevated levels of tyrosine phosphorylated B-catenin and the up-regulation of genes, including cyclin D1 and c-myc, which are associated with poor prognosis in patients with human breast cancers. These studies suggest that Ron overexpression may be a causative factor in breast tumorigenesis and provides a model to dissect the mechanism by which the Ron induces transformation and metastasis.

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“…Recent studies have indicated that altered RON expression contributes significantly to cancer progression and malignancy. In primary tumors, such as colon and breast cancers, overexpression of RON exists in a large number of cases and is often accompanied by the generation of different splicing variants (12)(13)(14). However, a comprehensive investigation of whether RON is involved in the formation of various types of tumors has not been adequately carried out.…”

Section: Introductionmentioning

confidence: 99%

Integrative genomic analyses of recepteur d’origine nantais and its prognostic value in cancer

Yuan

Chu

et al. 2013

International Journal of Molecular Medicine

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Abstract. Recepteur d'origine nantais (RON) is a receptor tyrosine kinase (RTK) normally expressed at low levels in epithelial cells. RON is a 180-kDa heterodimeric protein composed of a 40-kDa α-chain and a 150-kDa transmembrane β-chain with intrinsic tyrosine kinase activity. The extracellular sequences of RON contain several domains including an N-terminal semaphorin (sema) domain, followed by the plexin, semaphorin, integrin (PSI) domain, and four immunoglobulin, plexin, transcription factor (IPT) domains. Here, we identified RON genes from 14 vertebrate genomes and found that RON exists in all types of vertebrates including fish, amphibians, birds and mammals. We found that the human RON gene showed predominant expression in the liver, lymph node, thymus, intestine, lung, mammary gland, bone marrow, brain, heart, placenta, bladder, cortex, cervix, skin, kidney and prostate. When searched in the PrognoScan database, human RON was also found to be expressed in bladder, blood, breast, glioma, esophageal, colorectal, head and neck, ovarian, lung and skin cancer. The relationship between the expression of RON and prognosis was found to vary in different cancer types, even in the same cancer from different databases. This suggests that the function of RON in these tumors may be multidimensional, not just as a tumor suppressor or oncogene. Six available single-nucleotide polymorphisms (SNPs) disrupting existing exonic splicing enhancers were identified in RON. This may contribute to the generation of active RON variants by alternative splicing, which is frequently observed in primary tumors.

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Presence of RON receptor tyrosine kinase and its splicing variant in malignant and non-malignant human colonic mucosa.

Cited by 18 publications

References 0 publications

Alterations in a defined extracellular region of the RON receptor tyrosine kinase promote RON-mediated motile and invasive phenotypes in epithelial cells

Alterations in a defined extracellular region of the RON receptor tyrosine kinase promote RON-mediated motile and invasive phenotypes in epithelial cells

Mammary-Specific Ron Receptor Overexpression Induces Highly Metastatic Mammary Tumors Associated with β-Catenin Activation

Integrative genomic analyses of recepteur d’origine nantais and its prognostic value in cancer

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