title: Extracellular signal-regulated kinase (ERK) regulates cortactin ubiquitination and degradation in lung epithelial cells.
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.
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.forename: Jianxin
authors.initials: J
authors.lastname: Wei
authors.forename: Rachel
authors.initials: R
authors.lastname: Mialki
authors.forename: Chunbin
authors.initials: C
authors.lastname: Zou
authors.forename: Rama K
authors.initials: RK
authors.lastname: Mallampalli
authors.forename: Yutong
authors.initials: Y
authors.lastname: Zhao
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D002460:Cell Line; D051356:Cortactin / Q000235:genetics / Q000378:metabolism*; D003513:Cycloheximide / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D020125:Mutation, Missense; D055550:Protein Stability / Q000187:drug effects; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D059748:Proteolysis; D020545:Respiratory Mucosa / Q000166:cytology / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination / Q000502:physiology*; D044844:beta-Transducin Repeat-Containing Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D051356:Cortactin; C495869:Cttn protein, mouse; D008070:Lipopolysaccharides; D011500:Protein Synthesis Inhibitors; D044844:beta-Transducin Repeat-Containing Proteins; D003513:Cycloheximide; D044767:Ubiquitin-Protein Ligases; D048049:Extracellular Signal-Regulated MAP Kinases