Uncoupling Ligand-dependent and -independent Mechanisms for Mitogen-activated Protein Kinase Activation by the Murine Ron Receptor Tyrosine Kinase

Wei, Xin; Ni, Shuang; Correll, Pamela H.

doi:10.1074/jbc.m505737200

Cited by 21 publications

(26 citation statements)

References 45 publications

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“…These results strongly suggest that the mechanisms of RON activation by RON overexpression and by MSP stimulation are different in these RON-expressing MDCK cells. Noticeably, phosphorylation of ERK/ MAPK but not Akt was also recently reported for the mouse Stk [14].…”

Section: Ron Activation Leads To Erk/mapk But Not Akt Phosphorylationmentioning

confidence: 97%

Human RON receptor tyrosine kinase induces complete epithelial-to-mesenchymal transition but causes cellular senescence

Côté

Miller

Liu

2007

Biochemical and Biophysical Research Communications

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The RON receptor tyrosine kinase is a member of the MET proto-oncogene family and is important for cell proliferation, differentiation, and cancer development. Here we created a series of Madin-Darby canine kidney (MDCK) epithelial cell clones that express different levels of RON, and have investigated their biological properties. While low levels of RON correlated with little morphological change in MDCK cells, high levels of RON expression constitutively led to morphological scattering or complete and stabilized epithelial-to-mesenchymal transition (EMT). Unexpectedly, MDCK clones expressing higher levels of RON exhibited retarded proliferation and senescence, despite increased motility and invasiveness. RON was constitutively tyrosinephosphorylated in MDCK cells expressing high levels of RON and undergoing EMT, and the MAPK signaling pathway was activated. This study reveals for the first time that RON alone is sufficient to induce complete and stabilized EMT in MDCK cells, and overexpression of RON does not cause cell transformation but rather induce cell cycle arrest and senescence, leading to impaired cell proliferation.

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Section: Ron Activation Leads To Erk/mapk But Not Akt Phosphorylationmentioning

confidence: 97%

Human RON receptor tyrosine kinase induces complete epithelial-to-mesenchymal transition but causes cellular senescence

Côté

Miller

Liu

2007

Biochemical and Biophysical Research Communications

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“…We have recently shown that c-Src associates with mRON in a ligand-independent manner through three tyrosines in the kinase domain and that Src activity is required for the ligand-independent activation of MAP kinase by mRON (28). When the activation of AP1 by the mRON and hRON receptors was compared in SYF cells lacking all Src family kinases, there was no significant difference in the levels of constitutive signaling between hRON and mRON, and both receptors induced AP1 transcriptional activity in response to ligand stimulation (Fig.…”

Section: A Deletion In the Juxtamembrane Domain Of Hron Confers Liganmentioning

confidence: 99%

Altered Exon Usage in the Juxtamembrane Domain of Mouse and Human RON Regulates Receptor Activity and Signaling Specificity

Wei

Ni³

et al. 2005

Journal of Biological Chemistry

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Alternative splicing of signaling proteins can contribute to the complexity of signaling networks. We find that expression of mouse RON, but not human RON, results in constitutive receptor autophosphorylation, ligand-independent activation of the mitogen-activated protein kinase pathway, and association of the receptor with c-Src. Using chimeric receptors, we mapped the region for this difference in signaling capacity of mouse and human RON to the juxtamembrane domain. Expression of these receptors in primary erythroid progenitor cells also demonstrated a functional difference in the ability of mouse and human RON to support erythropoietin-independent colony formation that mapped to the juxtamembrane domain. Splicing of the mouse RON receptor tyrosine kinase transcript results in the constitutive deletion of an exon used by all other known RON orthologs that encodes part of the juxtamembrane domain of the receptor. Mutational analysis indicated that the two tyrosines present in this region in human RON, one of which has been previously shown to be a c-Cbl binding site, are not responsible for this difference. However, deletion of this region in the context of human RON enhanced receptor phosphorylation, activation of mitogen-activated protein kinase, and association of c-Src at levels comparable with those observed with mouse RON. These data provide direct evidence that the divergence of exon usage among different species can generate a protein with novel activity and subsequently add to the complexity of cellular signaling regulation.The modular nature of signaling proteins greatly facilitates the rapid evolution of a large number of molecules with various combinations of functional domains, increasing the possibility for combinatorial regulation. Furthermore, individual exons frequently correspond to basic folding and functional modules of a given protein (1). Expectedly, alternative splicing constitutes an important mechanism for protein evolution and diversification. By simply including or excluding certain exons, genes could reorganize their functional motifs to achieve novel activities without taking the risk of deleteriously mutating the coding sequence. Receptor tyrosine kinases (RTKs) 2 play a fundamental role in the regulation of animal development and pathogenesis. Intramolecular interactions, receptor dephosphorylation, and degradation form multiple layers of defense against uncontrolled kinase activity. The binding of growth factors enhances the enzymatic activity of the kinase domain by relieving structural constraints (2), resulting in tyrosine phosphorylation of the receptor that serves as an assembly platform for downstream signaling molecules (3). Alternative splicing, resulting in similar relief of these constraints, is one mechanism by which RTKs could become constitutively activated in tumor cells. Recent studies have identified several transforming transcripts of the human RON receptor tyrosine kinase, generated by alternative splicing of exons 5, 6, and 11 in the extracellular domain in pa...

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“…RON mutations were introduced using a QuikChange Mutagenesis kit (Stratagene) and then were subcloned into murine stem cell virus-derived retroviral transfer vector MSCV2.1 as previously described (25,26). Receptor expression was confirmed by immunoblotting (22) using a rabbit anti-RON polyclonal Ab (Santa Cruz Biotechnology) and mouse anti-GAPDH (Fitzgerald) as a loading control.…”

Section: Cells and Cell Linesmentioning

confidence: 99%

“…Therefore, to gain further insight into mechanisms by which RON repress HIV-1 provirus transcription we used site-directed mutagenesis to generate several mutations in the RON cytoplasmic domain (25,26). In particular, we mutated Y1353 and Y1360, which serve as a multifunctional docking site for several signaling molecules including Gab-1, Grb2, PI3K, phospholipase C, and Src homology protein-2 (32).…”

Section: Signals Emanating From Ron Inhibit Hiv Transcriptionmentioning

confidence: 99%

The Receptor Tyrosine Kinase RON Represses HIV-1 Transcription by Targeting RNA Polymerase II Processivity

Klatt

Zhang

Hankey

et al. 2008

The Journal of Immunology

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Efficient HIV-1 transcription requires the induction of cellular transcription factors, such as NF-κB, and the viral factor Tat, which through the recruitment of P-TEFb enhances processive transcription. However, whether cellular signals repress HIV-1 transcription to establish proviral latency has not been well studied. Previously, it has been shown that the receptor tyrosine kinase RON inhibits HIV transcription. To gain insights into the biochemical mechanisms by which RON inhibits transcription we examined the binding of transcription factors to the HIV provirus long terminal repeat using chromatin immunoprecipitation. RON expression decreased basal levels of NF-κB and RNA polymerase II (Pol II) binding to the HIV provirus long terminal repeat but did not prevent the induction of these complexes following treatment with cytokines. However, RON did decrease efficient transcription elongation because reduced RNA Pol II was associated with HIV-1 genomic sequences downstream of the transcriptional start site. There was a correlation between RON expression and increased binding of factors that negatively regulate transcription elongation, NELF, Spt5, and Pcf11. Furthermore, the ability of RON to inhibit HIV-1 transcription was sensitive to a histone deacetylase inhibitor and was associated with nucleosome remodeling. These results indicate that RON represses HIV transcription at multiple transcriptional check points including initiation, elongation and chromatin organization and are the first studies to show that cellular signaling pathways target Pol II pausing to repress gene expression.

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Uncoupling Ligand-dependent and -independent Mechanisms for Mitogen-activated Protein Kinase Activation by the Murine Ron Receptor Tyrosine Kinase

Cited by 21 publications

References 45 publications

Human RON receptor tyrosine kinase induces complete epithelial-to-mesenchymal transition but causes cellular senescence

Human RON receptor tyrosine kinase induces complete epithelial-to-mesenchymal transition but causes cellular senescence

Altered Exon Usage in the Juxtamembrane Domain of Mouse and Human RON Regulates Receptor Activity and Signaling Specificity

The Receptor Tyrosine Kinase RON Represses HIV-1 Transcription by Targeting RNA Polymerase II Processivity

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