Proteinase suppression by E-cadherin-mediated cell-cell attachment in premalignant oral keratinocytes.
The expression and activity of epithelial proteinases is under stringent control to prevent aberrant hydrolysis of structural proteins and disruption of tissue architecture. E-cadherin-dependent cell-cell adhesion is also important for maintenance of epithelial structural integrity, and loss of E-cadherin expression has been correlated with enhanced invasive potential in multiple tumor models. To address the hypothesis that there is a functional link between E-cadherin and proteinase expression, we have examined the role of E-cadherin in proteinase regulation. By using a calcium switch protocol to manipulate junction assembly, our data demonstrate that initiation of de novo E-cadherin-mediated adhesive contacts suppresses expression of both relative matrix metalloproteinase-9 levels and net urinary-type plasminogen activator activity. E-cadherin-mediated cell-cell adhesion increases both phosphatidylinositol 3'-kinase (PI3-kinase)-dependent AKT phosphorylation and epidermal growth factor receptor-dependent MAPK/ERK activation. Pharmacologic inhibition of the PI3-kinase pathway, but not the epidermal growth factor receptor/MAPK pathway, prevents E-cadherin-mediated suppression of proteinases and delays junction assembly. Moreover, inhibition of junction assembly with a function-blocking anti-E-cadherin antibody stimulates proteinase-dependent Matrigel invasion. As matrix metalloproteinase-9 and urinary-type plasminogen activator potentiate the invasive activity of oral squamous cell carcinoma, these data suggest E-cadherin-mediated signaling through PI3-kinase can regulate the invasive behavior of cells by modulating proteinase secretion.
Munshi
Hidayatullah G
HG
Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine and the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois 60611, USA.
Ghosh
Supurna
S
Mukhopadhyay
Subhendu
S
Wu
Yi I
YI
Sen
Ratna
R
Green
Kathleen J
KJ
Stack
M Sharon
MS
D000818:Animals; D015820:Cadherins / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002448:Cell Adhesion / Q000502:physiology*; D002460:Cell Line; D002614:Chelating Agents / Q000378:metabolism; D004533:Egtazic Acid / Q000378:metabolism; D010450:Endopeptidases / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009061:Mouth Mucosa / Q000166:cytology* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D011480:Protease Inhibitors / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism
D015820:Cadherins; D002118:Calcium; D002614:Chelating Agents; D004533:Egtazic Acid; D010450:Endopeptidases; D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D017395:Plasminogen Activator Inhibitor 1; D011480:Protease Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D019715:Tissue Inhibitor of Metalloproteinase-1; C494918:AKT1 protein, human