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Molecular and Cellular Biology, March 2003, p. 1786-1797, Vol. 23, No. 5
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.5.1786-1797.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Overexpression of Kinase Suppressor of Ras Upregulates the High-Molecular-Weight Tropomyosin Isoforms in ras-Transformed NIH 3T3 Fibroblasts

Richard A. J. Janssen,1,2,3* Phillia N. Kim,2 James W. Mier,3 and Deborah K. Morrison1

Regulation of Cell Growth Laboratory, National Cancer Institute—Frederick, Frederick, Maryland 21702,1 Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892,2 Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, Massachusetts 021153

Received 26 July 2002/ Returned for modification 10 October 2002/ Accepted 12 December 2002

The down-regulation of the high-molecular-weight isoforms of tropomyosin (TM) is considered to be an essential event in cellular transformation. In ras-transformed fibroblasts, the suppression of TM is dependent on the activity of the Raf-1 kinase; however, the requirement for other downstream effectors of Ras, such as MEK and ERK, is less clear. In this study, we have utilized the mitogen-activated protein kinase scaffolding protein Kinase Suppressor of Ras (KSR) to further investigate the regulation of TM and to clarify the importance of MEK/ERK signaling in this process. Here, we report that overexpression of wild-type KSR1 in ras-transformed fibroblasts restores TM expression and induces cell flattening and stress fiber formation. Moreover, we find that the transcriptional activity of a TM-{alpha} promoter is decreased in ras-transformed cells and that the restoration of TM by KSR1 coincides with increased transcription from this promoter. Although ERK activity was suppressed in cells overexpressing KSR1, ERK inhibition alone was insufficient to upregulate TM expression. The KSR1-mediated effects on stress fiber formation and TM transcription required the activity of the ROCK kinase, because these effects could be suppressed by the ROCK inhibitor, Y27632. Overexpression of KSR1 did not directly regulate ROCK activity, but did permit the recoupling of ROCK to the actin polymerization machinery. Finally, all of the KSR1-induced effects were mediated by the C-terminal domain of KSR1 and were dependent on the KSR-MEK interaction.

* Corresponding author. Present address: Nijmegen Center for Molecular Life Sciences, TIL 187, University Medical Center, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. Phone: 31 24 361 7485. Fax: 31 24 354 0339. r.janssen{at}ncmls.kun.nl.

Molecular and Cellular Biology, March 2003, p. 1786-1797, Vol. 23, No. 5
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.5.1786-1797.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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