The Extracellular Matrix Metalloproteinase Inducer (EMMPRIN, also called CD147) is highly expressed in multiple cancers, particularly in pancreatic cancer where it stimulates secretion of entire classes of proteins including matrix matelloproteinases (MMPs) and pro-inflammatory cytokines. Although, EMMPRIN was initially identified as a cellular transmembrane glycoprotein, extracellular EMMPRIN has recently emerged as a key player in disease progression. Though, little is known in regard to extracellular EMMPRIN, the role of glycans in its activity, and extracellular EMMPRIN's interactions with other proteins.
The aim of this study is to characterize glycosylated extracellular EMMPRIN in regard to its stimulatory activity of MMP/cytokine secretion (Aim 1) and target interactions (Aim 2), thereby unraveling a critical mechanism that underlies disease progression. The novelty of the proposed study comprises the combination of biological, biochemical, and atomic resolution methods to characterize extracellular EMMPRIN and the role that its glycans play in modulating EMMPRIN activity. Thus far, we have already developed recombinant expression systems to purify both unglycosylated and glycosylated extracellular EMMPRIN. Our biological studies have established that recombinant unglycosylated extracellular EMMPRIN stimulates the secretion of specific MMPs/cytokines. More recently, we have detected difference between unglycosylated and glycosylated extracellular EMMPRIN in regard to stimulation of MMP-9, which is critically involved in the development and progression of cancer. Thus, our preliminary studies have determined the functional influence of glycosylation on the activity of extracellular EMMPRIN, and we aim to fully characterize the activity profiles of unglycosylated and glycosylated extracellular EMMPRIN, the specific properties of EMMPRIN associated glycans and to begin characterizing the interaction partners of glycosylated and unglycosylated EMMPRIN. Since EMMPRIN over- expression results in the deregulation of entire protein families integrally involved in the progression of cancer, the combined biological, biochemical and biophysical approaches proposed here will allow for the characterization of extracellular EMMPRIN at the biological and molecular levels.

Public Health Relevance

Pancreatic cancer is the fourth leading cause of deaths in the United States and several pathways, implicated in the progression of pancreatic cancer are under the regulation of Extracellular Matrix Metalloproteinase Inducer (EMMPRIN). Although EMMPRIN was initially identified as a cellular transmembrane protein, extracellular form of EMMPRIN has recently emerged as a critical player in disease progression. The proposed studies are focused on fully characterizing extracellular EMMPRIN in regard to its stimulatory activity of MMP/cytokine secretion and target interactions, providing insight into pancreatic cancer disease progression and the identification of novel therapeutic targets.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
1F31CA180392-01
Application #
8593994
Study Section
Special Emphasis Panel (ZRG1-F05-D (21))
Program Officer
Damico, Mark W
Project Start
2013-08-01
Project End
2016-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
1
Fiscal Year
2013
Total Cost
$28,140
Indirect Cost
Name
University of Colorado Denver
Department
Biochemistry
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Kendrick, Agnieszka A; Holliday, Michael J; Isern, Nancy G et al. (2014) The dynamics of interleukin-8 and its interaction with human CXC receptor I peptide. Protein Sci 23:464-80