Abstract
During human prostate cancer progression, the integrin α6β1 (laminin receptor) is expressed on the cancer cell surface during invasion and in lymph node metastases. We previously identified a novel structural variant of the α6 integrin called α6p. This variant was produced on the cell surface and was missing the β-barrel extracellular domain. Using several different concentrations of amiloride, aminobenzamidine and PAI-1 and the urokinase-type plasminogen activator (uPA) function-blocking antibody (3689), we showed that uPA, acting as a protease, is responsible for production of α6p. We also showed that addition of uPA in the culture media of cells that do not produce α6p, resulted in a dose-dependent α6p production. In contrast, the addition of uPA did not result in the cleavage of other integrins. Using α2-antiplasmin and plasmin depleted media, we observed that uPA cleaves the α6 integrin directly. Further, 12-o-tetradecanoyl-phorbol-13-acetate (TPA) induced the production of α6p, and this induction was abolished by PAI-1 but not α2-antiplasmin. Finally, the α6p integrin variant was detected in invasive human prostate carcinoma tissue indicating that this is not a tissue culture phenomenon. These data, taken together, suggest that this is a novel function of uPA, that is, to remove the β-barrel ligand-binding domain of the integrin while preserving its heterodimer association.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 550-558 |
| Number of pages | 9 |
| Journal | Experimental Cell Research |
| Volume | 294 |
| Issue number | 2 |
| DOIs | |
| State | Published - Apr 1 2004 |
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Keywords
- Integrin
- Prostate cancer
- Urokinase
ASJC Scopus subject areas
- Cell Biology
Cite this
Extracellular alpha 6 integrin cleavage by urokinase-type plasminogen activator in human prostate cancer. / Demetriou, Manolis C.; Pennington, Michael E.; Nagle, Raymond B; Cress, Anne E.
In: Experimental Cell Research, Vol. 294, No. 2, 01.04.2004, p. 550-558.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Extracellular alpha 6 integrin cleavage by urokinase-type plasminogen activator in human prostate cancer
AU - Demetriou, Manolis C.
AU - Pennington, Michael E.
AU - Nagle, Raymond B
AU - Cress, Anne E
PY - 2004/4/1
Y1 - 2004/4/1
N2 - During human prostate cancer progression, the integrin α6β1 (laminin receptor) is expressed on the cancer cell surface during invasion and in lymph node metastases. We previously identified a novel structural variant of the α6 integrin called α6p. This variant was produced on the cell surface and was missing the β-barrel extracellular domain. Using several different concentrations of amiloride, aminobenzamidine and PAI-1 and the urokinase-type plasminogen activator (uPA) function-blocking antibody (3689), we showed that uPA, acting as a protease, is responsible for production of α6p. We also showed that addition of uPA in the culture media of cells that do not produce α6p, resulted in a dose-dependent α6p production. In contrast, the addition of uPA did not result in the cleavage of other integrins. Using α2-antiplasmin and plasmin depleted media, we observed that uPA cleaves the α6 integrin directly. Further, 12-o-tetradecanoyl-phorbol-13-acetate (TPA) induced the production of α6p, and this induction was abolished by PAI-1 but not α2-antiplasmin. Finally, the α6p integrin variant was detected in invasive human prostate carcinoma tissue indicating that this is not a tissue culture phenomenon. These data, taken together, suggest that this is a novel function of uPA, that is, to remove the β-barrel ligand-binding domain of the integrin while preserving its heterodimer association.
AB - During human prostate cancer progression, the integrin α6β1 (laminin receptor) is expressed on the cancer cell surface during invasion and in lymph node metastases. We previously identified a novel structural variant of the α6 integrin called α6p. This variant was produced on the cell surface and was missing the β-barrel extracellular domain. Using several different concentrations of amiloride, aminobenzamidine and PAI-1 and the urokinase-type plasminogen activator (uPA) function-blocking antibody (3689), we showed that uPA, acting as a protease, is responsible for production of α6p. We also showed that addition of uPA in the culture media of cells that do not produce α6p, resulted in a dose-dependent α6p production. In contrast, the addition of uPA did not result in the cleavage of other integrins. Using α2-antiplasmin and plasmin depleted media, we observed that uPA cleaves the α6 integrin directly. Further, 12-o-tetradecanoyl-phorbol-13-acetate (TPA) induced the production of α6p, and this induction was abolished by PAI-1 but not α2-antiplasmin. Finally, the α6p integrin variant was detected in invasive human prostate carcinoma tissue indicating that this is not a tissue culture phenomenon. These data, taken together, suggest that this is a novel function of uPA, that is, to remove the β-barrel ligand-binding domain of the integrin while preserving its heterodimer association.
KW - Integrin
KW - Prostate cancer
KW - Urokinase
UR - http://www.scopus.com/inward/record.url?scp=1542328915&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=1542328915&partnerID=8YFLogxK
U2 - 10.1016/j.yexcr.2003.11.023
DO - 10.1016/j.yexcr.2003.11.023
M3 - Article
C2 - 15023541
AN - SCOPUS:1542328915
VL - 294
SP - 550
EP - 558
JO - Experimental Cell Research
JF - Experimental Cell Research
SN - 0014-4827
IS - 2
ER -