Regulation of cell proliferation by ERK and signal-dependent nuclear translocation of ERK is dependent on Tm5NM1-containing actin filaments

Galina Schevzov, Anthony J. Kee, Bin Wang, Vanessa B. Sequeira, Jeff Hook, Jason D. Coombes, Christine A. Lucas, Justine R. Stehn, Elizabeth A. Musgrove, Alexandra Cretu, Richard Assoian, Thomas Fath, Tamar Hanoch, Rony Seger, Irina Pleines, Benjamin T. Kile, Edna C. Hardeman, Peter W. Gunning*

*Corresponding author for this work

Research output: Contribution to journalArticle

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ERK-regulated cell proliferation requires multiple phosphorylation events catalyzed first by MEK and then by casein kinase 2 (CK2), followed by interaction with importin7 and subsequent nuclear translocation of pERK. We report that genetic manipulation of a core component of the actin filaments of cancer cells, the tropomyosin Tm5NM1, regulates the proliferation of normal cells both in vitro and in vivo. Mouse embryo fibroblasts (MEFs) lacking Tm5NM1, which have reduced proliferative capacity, are insensitive to inhibition of ERK by peptide and small-molecule inhibitors, indicating that ERK is unable to regulate proliferation of these knockout (KO) cells. Treatment of wild-type MEFs with a CK2 inhibitor to block phosphorylation of the nuclear translocation signal in pERK resulted in greatly decreased cell proliferation and a significant reduction in the nuclear translocation of pERK. In contrast, Tm5NM1 KO MEFs, which show reduced nuclear translocation of pERK, were unaffected by inhibition of CK2. This suggested that it is nuclear translocation of CK2-phosphorylated pERK that regulates cell proliferation and this capacity is absent in Tm5NM1 KO cells. Proximity ligation assays confirmed a growth factor-stimulated interaction of pERK with Tm5NM1 and that the interaction of pERK with importin7 is greatly reduced in the Tm5NM1 KO cells.

Original languageEnglish
Pages (from-to)2475-2490
Number of pages16
JournalMolecular Biology of the Cell
Issue number13
Publication statusPublished - 1 Jul 2015
Externally publishedYes

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