Urokinase-type plasminogen activator binding to its receptor stimulates tumor cell migration by enhancing integrin-mediated signal transduction.
Urokinase-type plasminogen activator (uPA) and its receptor (uPAR) participate in matrix degradation and cell migration by focusing proteolysis and functioning as a signaling ligand/receptor complex. uPAR, anchored by a lipid moiety in the membrane, is thought to require a transmembrane adapter to transduce signals into the cytoplasm. To study uPAR signaling, we transfected the prostate carcinoma cell line LNCaP, which does not express endogenous uPA or uPAR, with a uPAR encoding cDNA, resulting in high-level surface expression. We studied migration of these cells on fibronectin, which is mediated by the integrin alpha5beta1. Ligation of uPAR with uPA or its amino-terminal fragment enhanced haptotactic migration to fibronectin. In cells on fibronectin, but not on poly-l-lysine, ligation of uPAR also resulted in tyrosine phosphorylation of several proteins, including two proteins involved in integrin signaling, focal adhesion kinase and the crk-associated substrate p130(Cas). Furthermore, after uPAR ligation, uPAR was co-immunoprecipitated with beta1 integrins from the detergent-insoluble fraction of cell lysates. Thus, our data suggest that uPAR occupancy results in an interaction between uPAR and integrins and a potentiation of integrin-mediated signaling, which leads to enhanced cell migration.
Yebra
M
M
Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines Road, IMM13, La Jolla, California, 92037, USA.
Goretzki
L
L
Pfeifer
M
M
Mueller
B M
BM
D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology*; D050719:Crk-Associated Substrate Protein; D005353:Fibronectins / Q000378:metabolism; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D006801:Humans; D008297:Male; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011471:Prostatic Neoplasms; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011506:Proteins; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D017469:Receptors, Fibronectin / Q000378:metabolism*; D055293:Receptors, Urokinase Plasminogen Activator; D050717:Retinoblastoma-Like Protein p130; D015398:Signal Transduction; D014162:Transfection; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*
C493841:BCAR1 protein, human; D015815:Cell Adhesion Molecules; D050719:Crk-Associated Substrate Protein; D005353:Fibronectins; C524898:PLAUR protein, human; D010750:Phosphoproteins; D011506:Proteins; D011956:Receptors, Cell Surface; D017469:Receptors, Fibronectin; D055293:Receptors, Urokinase Plasminogen Activator; D050717:Retinoblastoma-Like Protein p130; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; D014568:Urokinase-Type Plasminogen Activator