Urokinase receptor interacts with alpha(v)beta5 vitronectin receptor, promoting urokinase-dependent cell migration in breast cancer.
Perturbation of adhesive interactions at cell-substratum and cell-cell contact sites is a critical event in the multistep process of cancer invasion. Recent studies indicate that the urokinase receptor (uPAR) is associated in large molecular complexes with other molecules, such as integrins. To test the possibility that uPAR may physically and functionally interact with vitronectin (Vn) receptors, we determined the expression level of uPAR, alpha(v)beta3, and alpha(v)beta5 Vn receptors in 10 human breast carcinomas. Here, we show the ability of uPAR to physically associate with alpha(v)beta5 in the breast carcinomas examined. The functional effects of this interaction were studied using HT1080 human fibrosarcoma and MCF-7 human breast carcinoma cell lines, both exhibiting a urokinase-dependent physical association between uPAR and alpha(v)beta5. Both cell lines respond to urokinase or to its noncatalytic amino-terminal fragment by exhibiting remarkable cytoskeletal rearrangements that are mediated by alpha(v)beta5 and require protein kinase C activity. On the contrary, binding of Vn to alpha(v)beta5 results in the protein kinase C-independent formation of F-actin containing microspike-type structures. Furthermore, alpha(v)beta5 is required for urokinase-directed, receptor-dependent MCF-7 and HT1080 cell migration. These data show that uPAR association with alpha(v)beta5 leads to a functional interaction of these receptors and suggest that uPAR directs cytoskeletal rearrangements and cell migration by altering alpha(v)beta5 signaling specificity.
Carriero
M V
MV
National Cancer Institute, Naples, Italy. stoppelli@iigbna.iigb.na.cnr.it
Del Vecchio
S
S
Capozzoli
M
M
Franco
P
P
Fontana
L
L
Zannetti
A
A
Botti
G
G
D'Aiuto
G
G
Salvatore
M
M
Stoppelli
M P
MP
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000473:pathology*; D002465:Cell Movement; D005260:Female; D006801:Humans; D016023:Integrins / Q000502:physiology*; D008875:Middle Aged; D011493:Protein Kinase C / Q000502:physiology; D011956:Receptors, Cell Surface / Q000502:physiology*; D055293:Receptors, Urokinase Plasminogen Activator; D019030:Receptors, Vitronectin; D014407:Tumor Cells, Cultured; D014568:Urokinase-Type Plasminogen Activator / Q000502:physiology*; D019096:Vitronectin / Q000502:physiology
D016023:Integrins; C524898:PLAUR protein, human; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D019030:Receptors, Vitronectin; D019096:Vitronectin; C064660:integrin alphaVbeta5; D011493:Protein Kinase C; D014568:Urokinase-Type Plasminogen Activator