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Department of Specialty Care Services, The University of Texas Health Center at Tyler, Tyler, Texas 75708
Studies from our laboratory have shown that
exposure of human lung epithelial cells to urokinase plasminogen
activator (uPA) induces their proliferation. This effect of uPA is
likely to occur via activation of signal transduction pathways. To
elucidate uPA-induced signal transduction mechanisms, we exposed H-157
cells to uPA and determined the induced tyrosine phosphorylation
profile of proteins. We demonstrate that, in these cells, uPA
prominently induced tyrosine phosphorylation of a 78-kDa protein. This
effect was observed as early as 30 min and was sustained for at least 24 h. Treatment of cells with agents that abrogate uPA
receptor (uPAR) function, including neutralizing anti-uPAR antibody,
phosphatidylinositol-specific phospholipase C, or a selective
antagonist that blocks the association of uPA with uPAR (Å5
compound), all failed to prevent uPA-induced tyrosine phosphorylation.
B-428, an active site inhibitor of uPA activity, prevented the uPA
effect. Treatment of cells with hepatocyte growth factor, vascular
endothelial growth factor, or transforming growth factor-
, all of
which are known to be activated by a uPA-dependent pathway, did not
stimulate tyrosine phosphorylation of the 78-kDa protein. uPA induced
an increase in
[3H]thymidine
incorporation into DNA, and cell numbers were unaffected in the
presence of Å5. These results demonstrate that, in H-157 cells, uPA induces tyrosine phosphorylation of a 78-kDa protein via a
proteolysis-dependent but uPAR-independent mechanism. This novel
signaling pathway represents a putative mechanism by which uPA could
influence epithelial cell proliferation.
cell signaling; urokinase plasminogen activator receptor; tyrosine phosphorylation
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