The investigator has identified and characterized a human and rodent gene for which the cDNA codes for a protein with a domain structure similar to hepatocyte growth factor (HGF). The derived protein contains four kringle domains, followed by a serine protease-like domain, and has been termed """"""""HGF-like protein."""""""" Although the biologic properties of HGF as a mitogen, motogen and morphogen have been described, as well as growth suppressor function in some cell lines, the biologic properties of HGF-like protein have not yet been defined. In contrast, the HGF, which is expressed in many cell types including liver non-parenchymal or Ito cells, HGF-like protein as studied to date, is expressed primarily or at much higher levels in hepatocytes as compared to other tissues and is actively secreted into the circulation. Sequencing data has shown that this protein is identical to macrophage stimulating protein (MSP), and a cell surface tyrosine kinase receptor for HGF-like protein, referred to as Ron, has been identified. In contrast to the HGF-receptor, c-Met, which is also a cell surface tyrosine kinase, Ron is not expressed on hepatocytes. From these studies, Dr. Degen hypothesizes that HGF-like protein has diverse biologic properties similar to HGF, but exerts its effects on a different set of cell types. To test this hypothesis, she proposes the following specific aims: 1) to determine the cellular site(s) of synthesis and identification of cell lines expressing the Ron receptor; 2) to determine the mitogenic, chemotactic and motility properties of HGF-like protein using Ron expressing cell lines; 3) structure-function analysis of domains in HGF-like protein and the Ron receptor; and 4) to determine whether overexpression of HGF-like protein has a physiologic effect on Ron expressing tissue in the mouse. Ron expressing cell lines will be identified and used to determine the various biological properties of HGF-like protein. Structure-function studies will identify domain(s) responsible for specific functions and to determine whether different biological responses are elicited in a similar or different manner. The biological functions of HGF-like protein will be further investigated in normal and transgenic mice overexpressing HGF-like protein by studying models of liver regeneration, inflammation, wound healing and the acute phase response. These studies will determine the diversity of the biological properties of HGF-like protein and whether it is a growth factor with limited or broad specificity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK047003-05
Application #
2701135
Study Section
Metabolic Pathology Study Section (MEP)
Project Start
1994-05-10
Project End
2001-04-30
Budget Start
1998-07-10
Budget End
1999-04-30
Support Year
5
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
Hess, Karla Ann; Waltz, Susan E; Chan, Edward L et al. (2003) Receptor tyrosine kinase Ron is expressed in mouse reproductive tissues during embryo implantation and is important in trophoblast cell function. Biol Reprod 68:1267-75
Peace, Belinda E; Hill, Kara J; Degen, Sandra J F et al. (2003) Cross-talk between the receptor tyrosine kinases Ron and epidermal growth factor receptor. Exp Cell Res 289:317-25
McDowell, Susan A; Mallakin, Ali; Bachurski, Cindy J et al. (2002) The role of the receptor tyrosine kinase Ron in nickel-induced acute lung injury. Am J Respir Cell Mol Biol 26:99-104
Waltz, S E; Eaton, L; Toney-Earley, K et al. (2001) Ron-mediated cytoplasmic signaling is dispensable for viability but is required to limit inflammatory responses. J Clin Invest 108:567-76
Peace, B E; Hughes, M J; Degen, S J et al. (2001) Point mutations and overexpression of Ron induce transformation, tumor formation, and metastasis. Oncogene 20:6142-51
Muraoka, R S; Waltz, S E; Degen, S J (1999) Expression of hepatocyte growth factor-like protein is repressed by retinoic acid and enhanced by cyclic adenosine 3',5'-monophosphate response element-binding protein (CREB)-binding protein (CBP). Endocrinology 140:187-96
Muraoka, R S; Sun, W Y; Colbert, M C et al. (1999) The Ron/STK receptor tyrosine kinase is essential for peri-implantation development in the mouse. J Clin Invest 103:1277-85
Waltz, S E; Toms, C L; McDowell, S A et al. (1998) Characterization of the mouse Ron/Stk receptor tyrosine kinase gene. Oncogene 16:27-42
Degen, S J; McDowell, S A; Waltz, S E et al. (1998) Structure of the human D1F15S1A locus: a chromosome 1 locus with 97% identity to the chromosome 3 gene coding for hepatocyte growth factor-like protein. DNA Seq 8:409-13
Bezerra, J A; Carrick, T L; Degen, J L et al. (1998) Biological effects of targeted inactivation of hepatocyte growth factor-like protein in mice. J Clin Invest 101:1175-83

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