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TRANSFORMATION SENSITIVE PROTEIN WITH MOLECULAR WEIGHT OF 45,000 SECRETED BY MOUSE FIBROBLASTS
No full textA SPLICING VARIANT OF THE RON TRANSCRIPT INDUCES CONSTITUTIVE TYROSINE KINASE ACTIVITY AND INVASIVE PHENOTYPE
Full text linkRole of heterochromatin variation in the instability of a marker chromosome during tumor progression
No full textKaryotypic evolution of the poorly metastasizing tumorigenic RSV-transformed B77-3T3 fibroblast line was investigated both in highly metastasizing clones (selected by growth in hard agar) and in spontaneous metastases. Analysis of structural chromosome aberrations associated with the transition from the nonmetastatic to the metastatic phenotype was focused on a readily identifiable marker chromosome (A), displaying an extracentromeric heterochromatic region as a main feature promoting genetic instability. Well-defined changes in the structure of this marker were observed, both in vitro and in vivo, and invariably involved C-heterochromatic variation. In the metastatic clones, a specific rearrangement of the A chromosome was selected. This structural variant (B) showed two extracentromeric C-positive regions and probably originated from duplication of the segment of A included between the centromere and the internal C-band. On the other hand, selection of a modified form of chromosome A, not displaying the interpolated C-heterochromatin, had occurred in the extremely rare B77-3T3 spontaneous metastases. The connection among heterochromatin variants, genetic instability, and chromosome aberrations is discussed
The msp receptor gene (ron) is involved in development of epithelial, bone and neuro-endocrine tissues
No full textWe previously showed that the proto-oncogene RON encodes the tyrosine kinase receptor for Macrophage Stimulating Protein (MSP), originally isolated as a chemotactic factor for peritoneal macrophages. To elucidate the biological role of MSP we studied the expression of the Ron receptor in vivo, and the response to the factor in vitro. RON specific transcripts were detectable in mouse liver from early embryonal life (day 12.5 p.c.) through adult life. Adrenal gland, spinal ganglia, skin, lung and--unexpectedly--ossification centers of developing mandible, clavicle and ribs were also positive at later stages (day 13.5-16.5 p.c.). From day 17.5 RON was expressed in the gut epithelium and in a specific area of the central nervous system, corresponding to the nucleus of the hypoglossus. In adult mouse tissues RON transcripts were observed in brain, adrenal glands, gastro-intestinal tract, testis and kidney. Epithelial, osteoclast-like and neuroendocrine cells express the Ron receptor and respond to MSP in vitro. In the neuroendocrine PC12 cell line, while NGF induced growth arrest and morphological differentiation, MSP behaved as a strong mitogen. These findings show that the Ron receptor and its ligand are involved in the development of epithelial tissues, bones, and neuroendocrine derivatives driving cells towards the proliferation program
Metastatic clones selected from an RSV-induced mouse sarcoma share a common marker chromosome
No full textPrevious work has shown that the metastatic potential of RSV-transformed fibroblasts is correlated with the ability to form colonies in 0.6% ("hard") agar. Metastatic subclones were selected by this property from the non-metastasizing fibrosarcoma B77-313 line. A marker chromosome was found at high frequency (90% of cells) in all the subclones studied. This marker was detectable in only 0.5% of the parental B77-3T3 cells, demonstrating that metastatic clone precursors pre-existed, as a small minority, in the parental line. The genotypic marker appeared to be steadily associated with the metastatic phenotype since, after prolonged in vitro propagation, the subclones retained both the marker chromosome and the high metastatic potential. Although the marker chromosome was constantly present, chromosomal numerical and structural aberrations were also found in 20% of the long-term-propagated subclone cells, supporting the suggestion that metastatic properties are associated with cytogenetic instability
Biological activation of pro-HGF (hepatocyte growth factor) by urokinase is controlled by a stoichiometric reaction
No full textHepatocyte growth factor (HGF) is a paracrine inducer of morphogenesis and invasive growth in epithelial and endothelial cells. HGF is secreted by mesenchymal cells as an inactive precursor (pro-HGF). The crucial step for HGF activation is the extracellular hydrolysis of the Arg494-Val495 bond, which converts pro-HGF into alpha beta-HGF, the high-affinity ligand for the Met receptor. We previously reported that the urokinase-type plasminogen activator (uPA) activates pro-HGF in vitro. We now show that this is a stoichiometric reaction, and provide evidence for its occurrence in tissue culture. Activation involves the formation of a stable complex between pro-HGF and uPA. This complex was isolated from the in vitro reaction of pure uPA with recombinant pro-HGF, as well as from the membrane of target cells, after sequential addition of uPA and pro-HGF. On the cell membrane, the uPA-HGF complex was bound to the Met receptor. Monocytic cell lines, and primary monocytes after adhesion, activated efficiently pro-HGF both on their surface and in the culture medium. This activation was inhibited by anti-catalytic anti-uPA antibodies, and occurred by a stoichiometric reaction. The stoichiometry of the activation reaction suggests that the biological effects of HGF can be titrated in vivo by the level of uPA activity. Adequate amounts of uPA can be locally provided by the macrophages, which would condition the tissue microenvironment by rendering HGF bioavailable to its target cells
CONSTITUTIVE ACTIVATION OF THE RON GENE INDUCES INVASIVE GROWTH BUT NOT TRANSFORMATION
No full textMET, RON, and SEA are members of a gene family encoding tyrosine kinase receptors with distinctive properties. Besides mediating growth, they control cell dissociation, motility ('scattering'), and formation of branching tubules. While there are transforming counterparts of MET and SEA, no oncogenic forms of RON have yet been identified. A chimeric Tpr-Ron, mimicking the oncogenic form of Met (Tpr-Met) was generated to investigate its transforming potential. For comparison, a chimeric Tpr-Sea was also constructed. Fusion with Tpr induced constitutive activation of the Ron and Sea kinases. While Tpr-Sea was more efficient than Tpr-Met in transformation, Tpr-Ron did not transform NIH 3T3 cells. The differences in the transforming abilities of Tpr-Met and Tpr-Ron were linked to the functional features of the respective tyrosine kinases using the approach of swapping subdomains. Kinetic analysis showed that the catalytic efficiency of Tpr-Ron is five times lower than that of Tpr-Met. Moreover, constitutive activation of Ron resulted in activation of the MAP kinase signaling cascade approximately three times lower than that attained by Tpr-Met. However, constitutive activation of Ron did induce a mitogenic-invasive response, causing cell dissociation, motility, and invasion of extracellular matrices. Tpr-Ron also induced formation of long, unbranched tubules in tridimensional collagen gels. These data show that RON has the potential to elicit a motile-invasive rather than a transformed phenotype
A protein tyrosine phosphatase activity associated with the hepatocyte growth factor receptor
No full textHepatocyte growth factor induces proliferation and differentiation of multipotent hematopoietic progenitors
No full textHepatocyte growth factor (HGF) is a mesenchymal derived growth factor known to induce proliferation and "scattering" of epithelial and endothelial cells. Its receptor is the tyrosine kinase encoded by the c-MET protooncogene. Here we show that highly purified recombinant HGF stimulates hemopoietic progenitors to form colonies in vitro. In the presence of erythropoietin, picomolar concentrations of HGF induced the formation of erythroid burst-forming unit colonies from CD34-positive cells purified from human bone marrow, peripheral blood, or umbilical cord blood. The growth stimulatory activity was restricted to the erythroid lineage. HGF also stimulated the formation of multipotent CFU-GEMM colonies. This effect is synergized by stem cell factor, the ligand of the tyrosine kinase receptor encoded by the c-KIT protooncogene, which is active on early hemopoietic progenitors. By flow cytometry analysis, the receptor for HGF was found to be expressed on the cell surface in a fraction of CD34+ progenitors. Moreover, in situ hybridization experiments showed that HGF receptor mRNA is highly expressed in embryonic erythroid cells (megaloblasts). HGF mRNA was also found to be produced in the embryonal liver. These data show that HGF plays a direct role in the control of proliferation and differentiation of erythroid progenitors, and they suggest that it may be one of the long-sought mediators of paracrine interactions between stromal and hemopoietic cells within the hemopoietic microenvironment
Protein tyrosine phosphatase PTP-S binds to the juxtamembrane region of the hepatocyte growth factor receptor Met
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