Differential screening of a human chromosome 3 library identifies hepatocyte growth factor-like/macrophage-stimulating protein and its receptor in injured lung. Possible implications for neuroendocrine cell survival.

Willett, Christopher G.; Smith, Jeremy C.; Shridhar, Viji; Wang, Ming Hai; Emanuel, Rodica L.; Patidar, Kirit; Graham, S. A.; Zhang, Fan; Hatch, V.C.; Sugarbaker, David J.; Sunday, Mary E.

doi:10.1172/jci119493

Cited by 34 publications

(32 citation statements)

References 45 publications

(41 reference statements)

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“…Results presented herein demonstrate that Ron may limit the extent of inflammation by limiting the production of NO, one of the principle mediators of the inflammatory, microbicidal, and tumoricidal activity of macrophages, thus protecting tissues from the potentially damaging effects of NO and inflammation. Consistent with the hypothesis that Ron is a regulator of the macrophage-mediated inflammatory response is the fact that expression of the Ron ligand, HGFL, increases upon injury to the lungs and liver (33,34).…”

Section: Discussionsupporting

confidence: 55%

The Ron/STK receptor tyrosine kinase is essential for peri-implantation development in the mouse

Muraoka

Sun²,

Colbert³

et al. 1999

J. Clin. Invest.

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The Ron/STK receptor tyrosine kinase is a member of the c-Met family of receptors and is activated by hepatocyte growth factor-like protein (HGFL). Ron activation results in a variety of cellular responses in vitro, such as activation of macrophages, proliferation, migration, and invasion, suggesting a broad biologic role in vivo. Nevertheless, HGFL-deficient mice grow to adulthood with few appreciable phenotypic abnormalities. We report here that in striking contrast to the loss of its only known ligand, complete loss of Ron leads to early embryonic death. Embryos that are devoid of Ron (Ron -/-) are viable through the blastocyst stage of development but fail to survive past the peri-implantation period. In situ hybridization analysis demonstrates that Ron is expressed in the trophectoderm at embryonic day (E) 3.5 and is maintained in extraembryonic tissue through E7.5, compatible with an essential function at this stage of development. Hemizygous mice (Ron +/-) grow to adulthood; however, these mice are highly susceptible to endotoxic shock and appear to be compromised in their ability to downregulate nitric oxide production. These results demonstrate a novel role for Ron in early mouse development and suggest that Ron plays a limiting role in the inflammatory response. eration and motility of keratinocytes in vitro. The functions of Ron in vivo are not yet understood, but these findings suggest its involvement in a wide spectrum of biologic activities.An equally complex pattern of Ron expression is observed in the developing mouse, implying a functional requirement for Ron during embryogenesis. Ron expression is detected at embryonic day (E) 12.5 in the liver, perhaps reflecting fetal hematopoiesis, and in the central nervous system, primarily in the spinal and dorsal root ganglia. By E14.5, Ron expression has been initiated in the digestive tract epithelium, skin keratinocytes, and bone (22, 23). Information is not available on the expression of Ron prior to E7.5 in the mouse or on its expression in extraembryonic tissue.In spite of the growing body of evidence that Ron and HGFL are involved in embryogenesis and/or inflammation, HGFL-deficient mice grow to adulthood with few ascertainable defects, aside from the accumulation of lipid-filled cytoplasmic vesicles in hepatocytes, which does not perturb synthetic or secretory hepatic function (24). Activation of macrophages is delayed, but nevertheless attained, in the absence of HGFL, and hematopoiesis and wound healing appear to be unaltered in mice that are devoid of HGFL. To directly determine the specific functions of Ron in development and in the adult mouse, we have examined the consequences of Ron gene disruption in mice. In contrast to the loss of the ligand HGFL, we report that the complete loss of the Ron receptor tyrosine kinase leads to death in the periimplantation stage of development. MethodsDisruption of the mouse Ron gene. In construction of the targeting vector, exons 1-14 and part of exon 15 of the mouse Ron gene, isolated from a 129/Ola geno...

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Section: Discussionsupporting

confidence: 55%

The Ron/STK receptor tyrosine kinase is essential for peri-implantation development in the mouse

Muraoka

Sun²,

Colbert³

et al. 1999

J. Clin. Invest.

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“…Stimulation of Ron with its ligand HGFL increased ciliary beat frequency, and therefore Ron may play a role in mucociliary lung clearance. Ron has also been identified in small cell carcinoma of the lung (SCLC), in a pulmonary carcinoid cell line, and in a SCLC cell line (Willett et al, 1997). Ron was also examined in non-small-cell lung cancer (NSCLC) (Willett et al, 1998).…”

Section: G Lung Cancermentioning

confidence: 99%

Met‐Related Receptor Tyrosine Kinase Ron in Tumor Growth and Metastasis

Wagh

Peace

Waltz

2008

Advances in Cancer Research

143

168

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The Ron receptor is a member of the Met family of cell surface receptor tyrosine kinases and is primarily expressed on epithelial cells and macrophages. The biological response of Ron is mediated by binding of its ligand, hepatocyte growth factor-like protein/macrophage stimulatingprotein (HGFL). HGFL is primarily synthesized and secreted from hepatocytes as an inactive precursor and is activated at the cell surface. Binding of HGFL to Ron activates Ron and leads to the induction of a variety of intracellular signaling cascades that leads to cellular growth, motility and invasion. Recent studies have documented Ron overexpression in a variety of human cancers including breast, colon, liver, pancreas, and bladder. Moreover, clinical studies have also shown that Ron overexpression is associated with both worse patient outcomes as well as metastasis. Forced overexpression of Ron in transgenic mice leads to tumorigenesis in both the lung and the mammary gland and is associated with metastatic dissemination. While Ron overexpression appears to be a hallmark of many human cancers, the mechanisms by which Ron induces tumorigenesis and metastasis are still unclear. Several strategies are currently being undertaken to inhibit Ron as a potential therapeutic target; current strategies include the use of Ron blocking proteins, siRNA, monoclonal antibodies, and small molecule inhibitors. In total, these data suggest that Ron is a critical factor in tumorigenesis and that inhibition of this protein, alone or in combination with current therapies, may prove beneficial in the treatment of cancer patients.

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“…In addition to its effect in cell lines, recent studies have demonstrated that HGFL increases dramatically in wound fluids from human burn patients and that Ron expression is significantly upregulated during the wound healing response (Nanney et al, 1998). Further, Ron overexpression has been documented in a number of human cancers, including hepatocellular carcinomas (Chen et al, 1997), primary human non-small-cell lung carcinomas (Willett et al, 1997), malignant human colonic mucosa and breast carcinomas Maggiora et al, 1998;Okino et al, 1999;Wang et al, 2000). Our laboratory has recently shown that overexpression of wild-type Ron or activating mutations in Ron is sufficient to induce increased receptor phosphorylation and transformation of NIH3T3 cells to malignant phenotypes .…”

Section: Introductionmentioning

confidence: 99%

Ron tyrosine kinase receptor regulates papilloma growth and malignant conversion in a murine model of skin carcinogenesis

et al. 2004

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Recent studies demonstrate that the receptor tyrosine kinase (TK) Ron is tumorigenic when overexpressed and plays a role in regulating skin homeostasis. We hypothesized that Ron signaling promotes skin carcinogenesis. To test this hypothesis, mice deficient in the TK domain of Ron (TK À/À mice) were crossed with v-Ha-ras (Tg.AC) transgenic mice; the resulting TK À/À Tg.AC þ /À mice, and their controls, were utilized in a model of chemically induced Ras-mediated skin carcinogenesis. The mice were treated with 2.5 lg of 12-O-tetradecanoylphorbol-13-acetate applied weekly to the shaved back of 36 control (TK

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Differential screening of a human chromosome 3 library identifies hepatocyte growth factor-like/macrophage-stimulating protein and its receptor in injured lung. Possible implications for neuroendocrine cell survival.

Cited by 34 publications

References 45 publications

The Ron/STK receptor tyrosine kinase is essential for peri-implantation development in the mouse

The Ron/STK receptor tyrosine kinase is essential for peri-implantation development in the mouse

Met‐Related Receptor Tyrosine Kinase Ron in Tumor Growth and Metastasis

Ron tyrosine kinase receptor regulates papilloma growth and malignant conversion in a murine model of skin carcinogenesis

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