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Blood, 9 July 2009, Vol. 114, No. 2, pp. 338-345. Prepublished online as a Blood First Edition Paper on May 5, 2009; DOI 10.1182/blood-2009-02-200543. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2009-02-200543v1 114/2/338    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Google Scholar Articles by Xu, Y. Articles by Xie, W. PubMed PubMed Citation Articles by Xu, Y. Articles by Xie, W. Related Collections Immunobiology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Immunomodulatory drugs reorganize cytoskeleton by modulating Rho GTPases Yibing Xu1, Jianwu Li1, Gregory D. Ferguson1, Frank Mercurio1, Gody Khambatta1, Lisa Morrison1, Antonia Lopez-Girona1, Laura G. Corral1, David R. Webb1, Brydon L. Bennett1, and Weilin Xie1 1 Celgene, San Diego, CA IMiDs immunomodulatory drugs, including lenalidomide and pomalidomide represent a novel class of small molecule anticancer and anti-inflammatory drugs with broad biologic activities. However, the molecular mechanism through which these drugs exert their effects is largely undefined. Using pomalidomide and primary human monocytes, we report that pomalidomide rapidly and selectively activated RhoA and Rac1, but not Cdc42 or Ras, in the absence of any costimulation. Consistent with the activation of Rho GTPases, we found that pomalidomide enhanced F-actin formation, stabilized microtubules, and increased cell migration, all of which were blocked by selective inhibitors of ROCK1 and Rac1. Further, we showed that in Swiss 3T3 cells, pomalidomide only activated RhoA, not Rac1 or Cdc42, and potently induced stress fiber formation. The pomalidomide effect on actin cytoskeleton was blocked by the ROCK1 inhibitor, but not Rac1 inhibitor. Finally, we demonstrated that pomalidomide was able to regulate the activity of Rho GTPases and the formation of F-actin in primary human T cells as it did in monocytes and showed that the activation of RhoA was essential for pomalidomide-induced interleukin-2 expression in T cells. These novel activities provide what we believe a critical mechanism by which IMiDs drugs function as therapeutic immunomodulatory agents. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. G. Ramsay, A. J. Clear, G. Kelly, R. Fatah, J. Matthews, F. MacDougall, T. A. Lister, A. M. Lee, M. Calaminici, and J. G. Gribben Follicular lymphoma cells induce T-cell immunologic synapse dysfunction that can be repaired with lenalidomide: implications for the tumor microenvironment and immunotherapy Blood, November 19, 2009; 114(21): 4713 - 4720. [Abstract] [Full Text] [PDF]

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