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J Biol Chem, Vol. 275, Issue 18, 13789-13792, May 5, 2000
From the Departments of We have previously reported that
14,15-epoxyeicosatrienoic acid (14,15-EET) is a potent mitogen for the
renal epithelial cell line, LLCPKcl4. This mitogenic effect is
dependent upon activation of a protein-tyrosine kinase cascade that
results in activation of mitogen-activated protein kinase and
phosphatidylinositol 3-kinase. Because of suggestive evidence that
14,15-EET also activated Src in these cells, we stably transfected
LLCPKcl4 with an expression construct of the C-terminal Src kinase
(CSK), which inhibits Src family kinase activity. In vitro
Src kinase activity assays confirmed that in empty vector-transfected
cells (Vector cells), 14,15-EET increased Src kinase activity, while in
clones overexpressing CSK mRNA and immunoreactive protein (CSK
cells), 14,15-EET-induced activation of Src was almost completely
blocked (94% inhibition). Of interest, epidermal growth factor (EGF)
and fetal bovine serum (FBS) also increased Src activity in Vector
cells, but not in CSK cells, further confirming the ability of CSK
overexpression to prevent Src activation. CSK cells failed to increase
[3H]thymidine incorporation in response to exogenous
14,15-EET. In contrast, both EGF and FBS significantly increased
[3H]thymidine incorporation in CSK cells.
Immunoprecipitation with anti-phosphotyrosine antibodies and
immunoblotting with an antibody against extracellular signal-regulated
kinase (ERK) indicated that in CSK cells, 14,15-EET failed to activate
ERK1 and ERK2; however, EGF- and FBS-induced activation of ERKs was not
different from that seen in Vector cells. In Vector cells, the
14,15-EET-stimulated tyrosine phosphorylation of ERKs was blocked by
pretreatment with 1 µM PP2, a selective inhibitor of Src
kinases. The present study demonstrates that 14,15-EET exerts its
mitogenic effects predominantly through a Src kinase-mediated pathway,
which is the most upstream signaling step determined to date in the
14,15-EET-activated tyrosine kinase cascade in renal epithelial cells.
Overexpression of C-terminal Src Kinase Blocks
14,15-Epoxyeicosatrienoic Acid-induced Tyrosine Phosphorylation and
Mitogenesis*
,§, and¶
Medicine and
§ Biochemistry, Vanderbilt University,
Nashville, Tennessee 37232
*
This work was supported by National Institutes of Health
Grant DK38226.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
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