Cell surface-localized matrix metalloproteinase-9 proteolytically
activates TGF-beta and promotes tumor invasion and angiogenesis.

"MMP-9" "is a synonym for" "matrix metalloproteinase-9"
"cell surface" "is a location for" "MMP-9"
"cell surface MMP-9" "proteolytically activates" "TGF-beta"

"proteolytically active TGF-beta" "is a kind of" "TGF-beta"
"proteolytically active TGF-beta" "is a synonym for" "active TGF-beta"

"this" "authored by" "Yu Q"
"this" "authored by" "Stamenkovic I"

"this" "authored at" "Molecular Pathology Unit"
"this" "authored at" "Massachusetts General Hospital"
"this" "authored at" "Department of Pathology"
"this" "authored at" "Harvard Medical School"
"this" "authored at" "Boston"
"this" "authored at" "Massachusetts"
"this" "authored at" "02129"
"this" "authored at" "USA"

We have uncovered a novel functional relationship between the hyaluronan receptor CD44, the matrix metalloproteinase-9 (MMP-9) and the multifunctional cytokine TGF-beta in the control of tumor-associated tissue remodeling.

"hyaluronan receptor CD44" "is also known as" "CD44"
"hyaluronan receptor CD44" "has a functional relationship with" "MMP-9"
"hyaluronan receptor CD44" "has a functional relationship with" "TGF-beta"
"TGF-beta" "is a" "multifunctional cytokine"

CD44 provides a cell surface docking receptor for proteolytically active MMP-9 and we show here that localization of MMP-9 to cell surface is required for its ability to promote tumor invasion and angiogenesis.

"CD44" "is a" "cell surface receptor"
"active MMP-9" "docks to" "CD44"
"active MMP-9" "is a kind of" "MMP-9"
"CD44 MMP-9 complex" "promotes" "tumor invasion"
"CD44 MMP-9 complex" "promotes" "angiogenesis"
"CD44 MMP-9 complex" "contains" "CD44"
"CD44 MMP-9 complex" "contains" "MMP-9"

Our observations also indicate that MMP-9,
as well as MMP-2,
proteolytically cleaves latent TGF-beta,
providing a novel and potentially important mechanism for TGF-beta activation.

"MMP-9" "cleaves" "latent TGF-beta"
"latent TGF-beta" "is a kind of" "TGF-beta"
"MMP-2" "cleaves" "latent TGF-beta"
"latent TGF-beta" "when cleaved becomes" "active TGF-beta"

In addition, we show that MMP-9 localization to the surface of normal keratinocytes is CD44 dependent and can activate latent TGF-beta.

"MMP-9" "docks to" "normal keratinocytes"
"CD44 MMP-9 complex" "forms on" "normal keratinocytes"
"CD44 MMP-9 complex" "activates" "TGF-beta"

These observations suggest that coordinated CD44, MMP-9, and TGF-beta function may provide a physiological mechanism of tissue remodeling that can be adopted by malignant cells to promote tumor growth and invasion.

"CD44 MMP-9 TGF-beta coordination" "promotes growth of" "tumors"
"CD44 MMP-9 TGF-beta coordination" "promotes invasions by" "tumors"
"CD44 MMP-9 TGF-beta coordination" "promotes remodeling of" "tissue"

MeSH Terms:

Animal
Antigens,
CD44/physiology
Cell Membrane/enzymology
Culture Media,
Conditioned/pharmacology
Endothelium,
Vascular/pathology
Endothelium,
Vascular/enzymology
Gelatinase B/metabolism*
Hydrolysis
Keratinocytes/metabolism
Keratinocytes/enzymology
Male
Mammary Neoplasms,
Experimental/pathology
Mammary Neoplasms,
Experimental/enzymology
Mammary Neoplasms,
Experimental/blood supply*
Mice
Mice,
Inbred A
Mice,
Mutant Strains
Neoplasm Invasiveness
Neovascularization,
Pathologic/pathology
Neovascularization,
Pathologic/metabolism
Neovascularization,
Pathologic/enzymology*
Peptide Hydrolases/metabolism*
Protein Isoforms/metabolism
Support,
U.S.Gov't,P.H.S.
Transforming Growth Factor beta/metabolism*
Tumor Cells,
Cultured

Substances:

Transforming Growth Factor beta
Protein Isoforms
Culture Media,
Conditioned
Antigens,
CD44
Gelatinase B
Peptide Hydrolases

Grant support:

CA09216/CA/NCI
GM48614/GM/NIGMS
CA55375/CA/NCI

PMID: 10652271,
UI: 20119177