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Urokinase Plasminogen Activator Regulation of ERK, Stress Fiber Formation, and NHE in CCL39 Fibroblasts
Author(s) -
Magstadt Lisa K,
Provost Joseph J,
Wallert Mark A
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a982
Subject(s) - urokinase receptor , cell migration , microbiology and biotechnology , stress fiber , focal adhesion , mapk/erk pathway , extracellular matrix , signal transduction , cell adhesion , cytoskeleton , chemistry , lamellipodium , actin cytoskeleton , cell growth , receptor , biology , cell , biochemistry
Cell migration requires control of several signaling mechanisms including reorganization of the actin cytoskeleton and adhesion to the extracellular matrix. Urokinase plasminogen activator (uPA) is a thrombolytic agent that possesses a role both dependent and independent of binding to its receptor, uPAR. Receptor activation of uPAR localizes proteolytic activity to the leading edge of cellular migration and facilitates cellular penetration of tissue boundaries. Expression of both uPA and uPAR correlates with invasive cancer cell phenotype, however, the mechanism by which uPAR transduces its signals to regulate cell migration remains largely uncharacterized. Our focus is to investigate the signaling of uPA in CCL39 fibroblasts to determine a role for NHE in cytoskeletal remodeling and cell migratory events. ERK activation by uPA stimulation has been shown in a few cell lines. Smooth muscle cell inhibition of the sodium hydrogen exchanger (NHE) reduces cell proliferation and migration caused by uPA. Here we report that both the amino terminal fragment and recombinant uPA stimulate ERK phosphorylation in a bimodal fashion. The early peak of activity was observed within 5 min. and a later chronic stimulation of ERK was seen after 190 min. Both forms of uPA induced the formation of stress fibers in CCL39 fibroblasts and the amino terminal fragment of uPA induced over a 2 fold increase in NHE transport. These findings identify a potential new signaling role for uPA and suggest an important role for NHE in cell migration and invasion. This work was supported from a NIH Award 1 R15 HL074924‐01A1.