Urokinase induces activation of STAT3 in lung epithelial cells

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 exposure of human lung epithelial cells to uPA induces proliferation. To understand uPA mitogenic signaling events, we sought to elucidate its effects on tyrosine phosphorylation in a human bronchial epithelial cell line (Beas2B). uPA induced tyrosine phosphorylation of several proteins in a time-dependent manner. One of these proteins was identified as the 91-kDa signal transduction activator transcription (Stat)3 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 amino-terminal fragment 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 on its interaction with its receptor, uPAR, leading to DNA synthesis in lung epithelial cells.