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De novo synthesis of ß‐catenin via H‐Ras and MEK regulates airway smooth muscle growth
Author(s) -
Gosens Reinoud,
Baarsma Hoeke A.,
Heijink Irene H.,
Oenema Tjitske A.,
Halayko Andrew J.,
Meurs Herman,
Schmidt Martina
Publication year - 2010
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/fj.09-136325
Subject(s) - airway , catenin , microbiology and biotechnology , chemistry , biology , medicine , signal transduction , wnt signaling pathway , anesthesia
ß‐Catenin is a component of adherens junctions that also acts as a transcriptional coactivator when expressed in the nucleus. Growth factors are believed to regulate the nuclear expression of ß‐catenin via inactivation of glycogen synthase kinase 3 (GSK‐3) by phosphorylation, resulting in increased ß‐catenin protein stability. Here, we report on a novel pathway that regulates the expression and nuclear presence of ß‐catenin. In proliferating human airway smooth muscle cells, we observed increased expression of ß‐catenin, which was required for proliferation. Interestingly, increased ß‐catenin expression was accompanied by an increase in ß‐catenin mRNA and was independent of ß ‐catenin liberation from the plasma membrane, suggesting a role for de novo synthesis. This was confirmed using actinomycin D and cycloheximide, which abrogated the induction and nuclear localization of ß‐catenin protein. GSK‐3 inhibition using SB216763 failed to regulate ß‐catenin mRNA. However, expression of dominant negative H‐Ras or pharmacological inhibition of MEK reduced serum and TGF‐ß‐induced ß‐catenin mRNA and protein. Collectively, these data indicate that ß‐catenin is an important signaling intermediate in airway smooth muscle growth and that its cellular accumulation and nuclear localization require de novo protein synthesis effected, in part, via H‐Ras and MEK.—Gosens, R., Baarsma, H. A., Heijink, I. H., Oenema, T. A., Halayko, A. J., Meurs, H., Schmidt, M. De novo synthesis of ß‐catenin via H‐Ras and MEK regulates airway smooth muscle growth. FASEB J. 24, 757–768 (2010). www.fasebj.org