Urinary-type plasminogen activator (uPA) expression and uPA receptor localization are regulated by α3β1 integrin in oral keratinocytes

被引:69
作者
Ghosh, S
Brown, R
Jones, JCR
Ellerbroek, SM
Stack, MS
机构
[1] Northwestern Univ, Sch Med, Dept Obstet & Gynecol, Chicago, IL 60611 USA
[2] Northwestern Univ, Sch Med, Dept Cell & Mol Biol, Chicago, IL 60611 USA
[3] Northwestern Univ, Sch Med, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA
关键词
D O I
10.1074/jbc.M000935200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Expression of urinary-type plasminogen activator (uPA) and its receptor (uPAR) is correlated with matrix proteolysis, cell adhesion, motility, and invasion. To evaluate the functional link between adhesion and proteolysis in gingival keratinocytes (pp126), cells were treated with immobilized integrin antibodies to induce integrin clustering Clustering of alpha(3) and beta(1) integrin subunits, but not alpha(2), alpha(5), alpha(6), or beta(4), enhanced uPA secretion. Bead-immobilized laminin-5 and collagen I, two major alpha(3)beta(1) ligands, also induced uPA expression. Coordinate regulation of the serpin plasminogen activator inhibitor 1 was also apparent; however, a net increase in uPA activity was predominant. alpha(3)beta(1) integrin clustering induced extracellular signal-regulated kinase 1/2 phosphorylation, and both uPA induction and extracellular signal-regulated kinase activation were blocked by the mitogen-activated protein kinase/extracellular signal-regulated kinase kinase inhibitor PD98059, Integrin aggregation also promoted a dramatic redistribution of uPAR on the cell surface to sites of clustered alpha(3)beta(1) integrins. Co-immunoprecipitation of beta(1) integrin with uPAR provided further evidence that protein-protein interactions between uPAR and beta(1) integrin control uPAR distribution, As a functional consequence of uPA up-regulation and uPA-mediated plasminogen activation, the globular domain of the laminin-5 alpha(3) subunit, a major pp126 matrix protein, was proteolytically processed from a 190-kDa form to a 160-kDa species, Laminin-5 containing the 160-kDa alpha(3) subunit efficiently nucleates hemidesmosome formation and reduces cell motility, Together, these data suggest that multivalent aggregation of the alpha(3)beta(1) integrin regulates proteinase expression, matrix proteolysis, and subsequent cellular behavior.
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页码:23869 / 23876
页数:8
相关论文
共 49 条
[1]  
Andreasen PA, 1997, INT J CANCER, V72, P1, DOI 10.1002/(SICI)1097-0215(19970703)72:1<1::AID-IJC1>3.0.CO
[2]  
2-Z
[3]  
Baker SE, 1996, J CELL SCI, V109, P2509
[4]   Generation of monoclonal antibodies to integrin-associated proteins - Evidence that alpha(3)beta(1) complexes with EMMPRIN/basigin/OX47/M6 [J].
Berditchevski, F ;
Chang, S ;
Bodorova, J ;
Hemler, ME .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1997, 272 (46) :29174-29180
[5]   Extracellular matrix and integrin signalling: the shape of things to come [J].
Boudreau, J ;
Jones, PL .
BIOCHEMICAL JOURNAL, 1999, 339 :481-488
[6]   EPILIGRIN, A NEW CELL-ADHESION LIGAND FOR INTEGRIN ALPHA-3-BETA-1 IN EPITHELIAL BASEMENT-MEMBRANES [J].
CARTER, WG ;
RYAN, MC ;
GAHR, PJ .
CELL, 1991, 65 (04) :599-610
[7]   Plasminogen activators, integrins, and the coordinated regulation of cell adhesion and migration [J].
Chapman, HA .
CURRENT OPINION IN CELL BIOLOGY, 1997, 9 (05) :714-724
[8]  
CIAMBRONE GJ, 1992, J BIOL CHEM, V267, P13617
[9]  
Ellerbroek SM, 1999, CANCER RES, V59, P1635
[10]   Tumor dormancy induced by downregulation of urokinase receptor in human carcinoma involves integrin and MAPK signaling [J].
Ghiso, JAA ;
Kovalski, K ;
Ossowski, L .
JOURNAL OF CELL BIOLOGY, 1999, 147 (01) :89-103