Activation of hepatocyte growth factor and urokinase/plasminogen activator by matriptase, an epithelial membrane serine protease.
Matriptase is an epithelial-derived, integral membrane serine protease. The enzyme was initially isolated from human breast cancer cells and has been implicated in breast cancer invasion and metastasis. In the current study, using active matriptase isolated from human milk, we demonstrate that matriptase is able to cleave various synthetic substrates with arginine or lysine as their P1 sites and prefers small side chain amino acids, such as Ala and Gly, at P2 sites. For the most reactive substrates, N-tert-butoxycarbonyl (N-t-Boc)-gamma-benzyl-Glu-Ala-Arg-7-amino-4-methylcoumarin (AMC) and N-t-Boc-Gln-Ala-Arg-AMC, the K(m) values were determined to be 3. 81 and 4.89 microm, respectively. We further demonstrated that matriptase can convert hepatocyte growth factor/scattering factor to its active form, which can induce scatter of Madin-Darby canine kidney epithelial cells and can activate c-Met tyrosine phosphorylation in A549 human lung carcinoma cells. In addition, we noted that matriptase can activate urokinase plasminogen activator but has no affect on plasminogen. These results suggest that matriptase could act as an epithelial, upstream membrane activator to recruit and activate stromal-derived downstream effectors important for extracellular matrix degradation and epithelial migration, two major events of tissue remodeling, cancer invasion, and metastasis.
Lee
S L
SL
Department of Oncology, Lombardi Cancer Center, Georgetown University, Medical Center, Washington, DC 20007, USA.
Dickson
R B
RB
Lin
C Y
CY
D000818:Animals; D001120:Arginine / Q000378:metabolism; D002460:Cell Line; D004285:Dogs; D004789:Enzyme Activation; D004848:Epithelium / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000378:metabolism; D010766:Phosphorylation; D011994:Recombinant Proteins / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism*; D014357:Trypsin / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*
D011994:Recombinant Proteins; D014443:Tyrosine; D017228:Hepatocyte Growth Factor; D001120:Arginine; D012697:Serine Endopeptidases; C485595:matriptase; C485596:ST14 protein, human; D014357:Trypsin; D014568:Urokinase-Type Plasminogen Activator; D008239:Lysine; C067551:saruplase