Abstract
Cortactin, an actin-binding protein, is essential for cell growth and motility. We have shown that cortactin is regulated by reversible phosphorylation, but little is known regarding cortactin protein stability. Here, we show that lipopolysaccharide (LPS)-induced cortactin degradation is mediated by extracellular regulated signal kinase (ERK). LPS induces cortactin serine phosphorylation, ubiquitination, and degradation in mouse lung epithelia, an effect abrogated by ERK inhibition. Serine phosphorylation sites mutant, cortactin(S405A/S418A), enhances its protein stability. Cortactin is polyubiquitinated and degraded within the proteasome, whereas a cortactin(K79R) mutant exhibited proteolytic stability during cyclohexamide (CHX) or LPS treatment. The E3 ligase subunit β-Trcp interacts with cortactin, and its overexpression reduced cortactin protein levels, an effect attenuated by ERK inhibition. Overexpression of β-Trcp was sufficient to reduce the protective effects of exogenous cortactin on epithelial cell barrier integrity, an effect not observed after expression of a cortactin(K79R) mutant. These results provide evidence that LPS modulation of cortactin stability is coordinately regulated by stress kinases and the ubiquitin-proteasomal network.
Highlights
The E3 ligase subunit -Trcp interacts with cortactin, and its overexpression reduced cortactin protein levels, an effect attenuated by extracellular regulated signal kinase (ERK) inhibition
Cortactin Degradation Is Mediated by Ubiquitin-Proteasome System—To investigate the mechanisms of cortactin degradation, we first examined the stability of cortactin in MLE12 cells
Cortactin activity controlled by post-translational modifications, such as phosphorylation [23, 24] and acetylation [44], has been studied extensively; understanding of cortactin protein stability is limited
Summary
Overexpression of -Trcp was sufficient to reduce the protective effects of exogenous cortactin on epithelial cell barrier integrity, an effect not observed after expression of a cortactinK79R mutant. These results provide evidence that LPS modulation of cortactin stability is coordinately regulated by stress kinases and the ubiquitin-proteasomal network. ERK-dependent serine phosphorylation of cortactin is essential for cortactin ubiquitination and degradation in response to lipopolysaccharide (LPS) These results provide evidence that cortactin protein stability is regulated by the combinatorial activities of ERK and -Trcp as key bioeffectors controlling epithelial barrier function
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