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Mol Biol Cell. 2015 Jul 1;26(13):2475-90. doi: 10.1091/mbc.E14-10-1453. Epub 2015 May 13.

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

Author information

1
Oncology Research Unit, School of Medical Sciences, University of New South Wales, Australia, Sydney, NSW 2052, Australia.
2
Cellular and Genetic Medicine Unit, University of New South Wales, Australia, Sydney, NSW 2052, Australia.
3
Oncology Research Unit, School of Medical Sciences, University of New South Wales, Australia, Sydney, NSW 2052, Australia Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia.
4
Kinghorn Cancer Centre, Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia.
5
Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6160.
6
Neurodegeneration and Repair Laboratory, School of Medical Sciences, University of New South Wales, Australia, Sydney, NSW 2052, Australia.
7
Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
8
Cancer and Hematology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
9
Oncology Research Unit, School of Medical Sciences, University of New South Wales, Australia, Sydney, NSW 2052, Australia p.gunning@unsw.edu.au.

Abstract

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.

PMID:
25971798
PMCID:
PMC4571302
DOI:
10.1091/mbc.E14-10-1453
[Indexed for MEDLINE]
Free PMC Article

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