This research project focuses on the urokinase receptor (uPAR), a multifunctional GPI-anchored membrane protein that has been implicated in breast cancer progression. Our long-term goal is to understand mechanisms by which uPAR regulates cancer cell physiology. uPAR binds at least two ligands: the plasminogen activator, urokinase-type plasminogen activator (uPA), and the provisional extracellular matrix protein, vitronectin. Within the plasma membrane, uPAR laterally associates with integrins, G-protein coupled receptors, and receptor-tyrosine kinases (RTKs). These "co-receptor" interactions result in the formation of a dynamic, multiprotein signaling receptor complex (MSRC). uPA and vitronectin activate uPAR-dependent cell signaling;however, the pathways are distinct. uPA-binding activates ERK/MAP kinase whereas vitronectin activates Rad. Other signaling proteins, such as STAT-5b, may be recruited downstream of uPAR depending on the co-receptors that associate with uPAR in the MSRC. Co-receptors also determine the nature of the cellular response, such as whether uPA is mitogenic. In this application, four specific aims are proposed.
In Aim 1, we propose to elucidate the pathway that leads from uPAR to Rac1 and determine the mechanism by which ligation of a single receptor (uPAR) with two distinct ligands (uPA or vitronectin) causes completely distinct cell signaling responses.
Aim 2 builds on preliminary data in which we have demonstrated that uPAR over-expression induces epithelial-mesenchymal transformation (EMT), a well known process associated with cancer progression in which epithelial cells adopt a fibroblast-like morphology, lose cell-cell contacts, demonstrate increased vimentin expression and decreased E-cadherin expression. Experiments planned in Aim 2 will determine the mechanism by which uPAR induces EMT.
In Aim 3, we will test the hypothesis that uPAR-dependent cell signaling regulates the response of cancer cells not only to uPA but also to growth factors such as EGF and PDGF. Understanding crosstalk between uPAR and RTKs is a critical objective. Finally, in Aim 4, we propose studies to determine whether uPAR-dependent cell signaling is involved in cancer development and progression in vivo. Xenograft and spontaneous neoplasia mouse-model systems will be applied. These studies will elucidate the role of uPAR in cancer and provide critical information regarding how uPAR may be targeted for novel cancer therapeutics design.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA094900-11
Application #
8019109
Study Section
Hemostasis and Thrombosis Study Section (HT)
Program Officer
Ault, Grace S
Project Start
2002-04-01
Project End
2012-08-31
Budget Start
2011-03-01
Budget End
2012-08-31
Support Year
11
Fiscal Year
2011
Total Cost
$259,520
Indirect Cost
Name
University of California San Diego
Department
Pathology
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Eastman, Boryana M; Jo, Minji; Webb, Drue L et al. (2012) A transformation in the mechanism by which the urokinase receptor signals provides a selection advantage for estrogen receptor-expressing breast cancer cells in the absence of estrogen. Cell Signal 24:1847-55
Gonias, Steven L; Gaultier, Alban; Jo, Minji (2011) Regulation of the urokinase receptor (uPAR) by LDL receptor-related protein-1 (LRP1). Curr Pharm Des 17:1962-9
Hu, Jingjing; Jo, Minji; Cavenee, Webster K et al. (2011) Crosstalk between the urokinase-type plasminogen activator receptor and EGF receptor variant III supports survival and growth of glioblastoma cells. Proc Natl Acad Sci U S A 108:15984-9
Gaultier, Alban; Hollister, Margaret; Reynolds, Irene et al. (2010) LRP1 regulates remodeling of the extracellular matrix by fibroblasts. Matrix Biol 29:22-30
Jo, Minji; Eastman, Boryana M; Webb, Drue L et al. (2010) Cell signaling by urokinase-type plasminogen activator receptor induces stem cell-like properties in breast cancer cells. Cancer Res 70:8948-58
Green, Chad E; Liu, Tiffany; Montel, Valerie et al. (2009) Chemoattractant signaling between tumor cells and macrophages regulates cancer cell migration, metastasis and neovascularization. PLoS One 4:e6713
Jo, Minji; Lester, Robin D; Montel, Valerie et al. (2009) Reversibility of epithelial-mesenchymal transition (EMT) induced in breast cancer cells by activation of urokinase receptor-dependent cell signaling. J Biol Chem 284:22825-33
Jo, Minji; Takimoto, Shinako; Montel, Valerie et al. (2009) The urokinase receptor promotes cancer metastasis independently of urokinase-type plasminogen activator in mice. Am J Pathol 175:190-200
Montel, Valerie; Gaultier, Alban; Lester, Robin D et al. (2007) The low-density lipoprotein receptor-related protein regulates cancer cell survival and metastasis development. Cancer Res 67:9817-24
Lester, Robin D; Jo, Minji; Montel, Valerie et al. (2007) uPAR induces epithelial-mesenchymal transition in hypoxic breast cancer cells. J Cell Biol 178:425-36

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