Gj. Bhat et al., Urokinase-type plasminogen activator induces tyrosine phosphorylation of a78-kDa protein in H-157 cells, AM J P-LUNG, 21(2), 1999, pp. L301-L309
Citations number
23
Categorie Soggetti
da verificare
Journal title
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY
Studies from our laboratory have shown that exposure of human lung epitheli
al cells to urokinase plasminogen activator (uPA) induces their proliferati
on. This effect of uPA is likely to occur via activation of signal transduc
tion pathways. To elucidate uPA-induced signal transduction mechanisms, we
exposed H-157 cells to uPA and determined the induced tyrosine phosphorylat
ion profile of proteins. We demonstrate that, in these cells, uPA prominent
ly induced tyrosine phosphorylation of a 78-kDa protein. This effect was ob
served 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 ne
utralizing anti-uPAR antibody, phosphatidylinositol-specific phospholipase
C, or a selective antagonist that blocks the association of uPA with uPAR (
Angstrom 5 compound), all failed to prevent uPA-induced tyrosine phosphoryl
ation. B-428, an active site inhibitor of uPA activity, prevented the uPA e
ffect. Treatment of cells with hepatocyte growth factor, vascular endotheli
al growth factor, or transforming growth factor-beta, all of which are know
n to be activated by a uPA-dependent pathway, did not stimulate tyrosine ph
osphorylation of the 78-kDa protein. uPA induced an increase in [H-3]thymid
ine incorporation into DNA, and cell numbers were unaffected in the presenc
e of Angstrom 5. These results demonstrate that, in H-157 cells, uPA induce
s tyrosine phosphorylation of a 78-kDa protein via a proteolysis-dependent
but uPAR-independent mechanism. This novel signaling pathway represents a p
utative mechanism by which uPA could influence epithelial cell proliferatio
n.