RON (Recepteur d'Origine Nantais) or alternatively STK (stem cell derived tyrosine kinase) is a novel receptor tyrosine kinase belonging to the Met proto-oncogene family. The only known ligand for RON is MSP (macrophage stimulating protein). MSP is constitutively expressed in liver and circulates as an inactive form requiring proteolytic conversion for activation. Activation of RON by MSP stimulates macrophage shape change, chemotactic migration, and phagocytosis, however, RON activation also results in blocking endotoxin or cytokine-induced expression of inducible nitric oxide synthase (iNOS) by murine peritoneal macrophages, suggesting a dual role in inflammation. Expression of iNOS is required for bactericidal and tumoricidal actions of macrophages. However, NO is also an important cause of tissue destruction in inflammation and mediates some of the adverse hemodynamic consequences of septic shock. Therefore, understanding the mechanisms of iNOS expression by macrophages is important and likely to be clinically useful. The hypotheses underlying this proposal are that: 1) RON expression is regulated such that not all populations of tissue-derived macrophages express RON; 2) RON activation inhibits iNOS expression at the transcription level; 3) Specific inhibition of iNOS is determined by the intracellular domains of RON that transduce a unique signaling pathway. To test these hypotheses, the expression and activation of RON in regulation of LPS or IFN-gamma-induced iNOS synthesis by different types of tissue macrophages will be determined. The effect of RON activation on IFN-gamma or LPS-induced signaling pathways essential for macrophage iNOS expression will be studied. And the potential tyrosine-containing domains in the RON C-terminal tail that transduce iNOS inhibitory signals will be identified. The applicant proposes that this work is important for several reasons. First, it will provide the basis for better understanding of iNOS regulation by endogenously produced inhibitors. Second it will facilitate understanding of the role of MSP in regulating macrophage activities in inflammation. Further, this work may lead to novel approaches for decreasing tissue destruction in inflammation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI043516-04
Application #
6170557
Study Section
Pathology A Study Section (PTHA)
Program Officer
Kraemer, Kristy A
Project Start
1998-09-01
Project End
2002-08-31
Budget Start
2000-09-01
Budget End
2001-08-31
Support Year
4
Fiscal Year
2000
Total Cost
$208,982
Indirect Cost
Name
University of Colorado Denver
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045
Zhou, Yong-Qing; He, Chao; Chen, Yi-Qing et al. (2003) Altered expression of the RON receptor tyrosine kinase in primary human colorectal adenocarcinomas: generation of different splicing RON variants and their oncogenic potential. Oncogene 22:186-97
Wang, Ming-Hai; Wang, Da; Chen, Yi-Qing (2003) Oncogenic and invasive potentials of human macrophage-stimulating protein receptor, the RON receptor tyrosine kinase. Carcinogenesis 24:1291-300
Zhou, Yong-Qing; Chen, Yi-Qing; Fisher, James H et al. (2002) Activation of the RON receptor tyrosine kinase by macrophage-stimulating protein inhibits inducible cyclooxygenase-2 expression in murine macrophages. J Biol Chem 277:38104-10
Wang, M-H; Zhou, Y-Q; Chen, Y-Q (2002) Macrophage-stimulating protein and RON receptor tyrosine kinase: potential regulators of macrophage inflammatory activities. Scand J Immunol 56:545-53
Chen, Yi-Qing; Zhou, Yong-Qing; Fisher, James H et al. (2002) Targeted expression of the receptor tyrosine kinase RON in distal lung epithelial cells results in multiple tumor formation: oncogenic potential of RON in vivo. Oncogene 21:6382-6
Chen, Y Q; Zhou, Y Q; Angeloni, D et al. (2000) Overexpression and activation of the RON receptor tyrosine kinase in a panel of human colorectal carcinoma cell lines. Exp Cell Res 261:229-38
Xiao, Z Q; Chen, Y Q; Wang, M H (2000) Requirement of both tyrosine residues 1330 and 1337 in the C-terminal tail of the RON receptor tyrosine kinase for epithelial cell scattering and migration. Biochem Biophys Res Commun 267:669-75
Wang, M H; Fung, H L; Chen, Y Q (2000) Regulation of the RON receptor tyrosine kinase expression in macrophages: blocking the RON gene transcription by endotoxin-induced nitric oxide. J Immunol 164:3815-21
Wang, M H; Kurtz, A L; Chen, Y (2000) Identification of a novel splicing product of the RON receptor tyrosine kinase in human colorectal carcinoma cells. Carcinogenesis 21:1507-12
Chen, Y Q; Fisher, J H; Wang, M H (1998) Activation of the RON receptor tyrosine kinase inhibits inducible nitric oxide synthase (iNOS) expression by murine peritoneal exudate macrophages: phosphatidylinositol-3 kinase is required for RON-mediated inhibition of iNOS expression. J Immunol 161:4950-9