Soluble extracellular matrix metalloproteinase inducer (EMMPRIN, EMN) regulates cancer-related cellular functions by homotypic interactions with surface CD147.
EMMPRIN (extracellular matrix metalloproteinase inducer) is a widely expressed glycoprotein and a member of the immunoglobulin superfamily which exists in both a membrane-spanning and a soluble form. Homotypic interactions of EMMPRIN underlie its multiple roles in normal development and pathological situations such as viral infections, Alzheimer's disease and cancer. This study employed a recombinant soluble, fully glycosylated EMMPRIN domain (rhsEMN) as a tool to characterize the structural basis of EMMPRIN-EMMPRIN receptor (EMNR) contacts and their functional effects on MCF-7 breast carcinoma cells. rhsEMN did not form dimers in solution but bound to surface EMMPRIN (EMN) on MCF-7 cells with high affinity and was readily internalized. The interaction interface for the homotypic contact was localized to the N-terminal Ig domain. rhsEMN exerted a stimulatory effect on proliferation of MCF-7 cells whereas it reduced cell migration in a dose-dependent manner. These effects were accompanied by an upregulation of endogenous EMMPRIN as well as of matrix metalloproteinase-14 (MMP-14), a membrane-bound protease involved in the extracellular release of soluble EMMPRIN, indicating a regulatory feedback mechanism. The proliferation-promoting activity of rhsEMN was mimicked by a novel functional antibody directed to EMMPRIN, underscoring that crosslinking of cell surface EMMPRIN (EMNR) is crucial for eliciting intracellular signalling. Addressing malignancy-related signal transduction in HEK-293 cells, we could show that rhsEMN triggers the oncogenic Wnt pathway.
Institute of Biochemistry II, Jena University Hospital, Germany.
Nadine
N
Knutti
Department of Pneumology, University of Rostock, Germany.
Michael
M
Kuepper
Institute of Biochemistry II, Jena University Hospital, Germany.
Karlheinz
K
Friedrich
D051926:Basigin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D005260:Female; D006031:Glycosylation; D057809:HEK293 Cells; D006801:Humans; D061986:MCF-7 Cells; D053511:Matrix Metalloproteinase 14 / Q000096:biosynthesis / Q000235:genetics; D017434:Protein Structure, Tertiary; D011946:Receptors, Antigen / Q000737:chemistry / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012995:Solubility; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism
C497886:BSG protein, human; C495270:CTNNB1 protein, human; D011946:Receptors, Antigen; D011994:Recombinant Proteins; D051176:beta Catenin; D051926:Basigin; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14
MMPs; Wnt pathway; breast cancer; membrane proteins; protein glycosylation