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1 Specialty Care Services, The University of Texas Health Center at Tyler, Tyler, Texas, United States
* To whom correspondence should be addressed. E-mail: sreerama.shetty{at}uthct.edu.
Urokinase-type plasminogen activator (uPA) is a serine protease that plays a major role in diverse physiological and pathological processes. Studies from our laboratory have shown that the exposure of human lung epithelial cells to uPA induces proliferation. In order to understand uPA mitogenic signaling events, we sought to elucidate its effects on tyrosine phosphorylation in Beas2B cells. uPA induced tyrosine phosphorylation of several proteins in a time-dependent manner. One of these proteins was identified as the 91 kDa Stat3 moiety. Tyrosine phosphorylation of Stat3 by uPA was time-dependent. uPA induced Stat3-DNA binding activity in a time-dependent manner. uPA-induced Stat3 activation does not require uPA catalytic activity as the uPA aminoterminal fragment (ATF) alone was as potent as active two-chain uPA (tcuPA) in causing this effect. Single-chain uPA likewise induced tyrosine phosphorylation of Stat3 to a similar extent as intact tcuPA. Plasmin did not alter uPA-induced Stat3 activation. Furthermore transfection of Beas2B cells with dominant negative Stat3 blocked uPA-induced DNA synthesis. These results reveal for the first time that the uPA-uPAR interaction leads to activation of Stat3 independent of its catalytic activity but dependent upon its interaction with its receptor, uPAR, leading to DNA synthesis in lung epithelial cells.
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