Article abstract


Nature Chemical Biology 2, 39 - 46 (2005)
Published online: 20 November 2005 | Corrected online: 1 July 0603 | doi:10.1038/nchembio751



There is an Erratum (April 2006) associated with this Article.

Secramine inhibits Cdc42-dependent functions in cells and Cdc42 activation in vitro

Henry E Pelish1,2,3, Jeffrey R Peterson4, Susana B Salvarezza5, Enrique Rodriguez-Boulan5, Ji-Long Chen6, Mark Stamnes6, Eric Macia1, Yan Feng3,7, Matthew D Shair2,3 & Tomas Kirchhausen1,3


Inspired by the usefulness of small molecules to study membrane traffic, we used high-throughput synthesis and phenotypic screening to discover secramine, a molecule that inhibits membrane traffic out of the Golgi apparatus by an unknown mechanism. We report here that secramine inhibits activation of the Rho GTPase Cdc42, a protein involved in membrane traffic, by a mechanism dependent upon the guanine dissociation inhibitor RhoGDI. RhoGDI binds Cdc42 and antagonizes its membrane association, nucleotide exchange and effector binding. In vitro, secramine inhibits Cdc42 binding to membranes, GTP and effectors in a RhoGDI-dependent manner. In cells, secramine mimics the effects of dominant-negative Cdc42 expression on protein export from the Golgi and on Golgi polarization in migrating cells. RhoGDI-dependent Cdc42 inhibition by secramine illustrates a new way to inhibit Rho GTPases with small molecules and provides a new means to study Cdc42, RhoGDI and the cellular processes they mediate.

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  1. Department of Cell Biology and the CBR Institute for Biomedical Research, Harvard Medical School, 200 Longwood Avenue, Boston, Massachusetts 02115, USA.
  2. Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, USA.
  3. Harvard Institute of Chemistry and Cell Biology, Harvard Medical School, 250 Longwood Avenue, Boston, Massachusetts 02115, USA.
  4. Division of Basic Sciences, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
  5. Dyson Vision Research Institute, Weill Medical College of Cornell University, New York, New York 10021, USA.
  6. University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA.
  7. Present address: Functional Genomics, 5B-274, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.

Correspondence to: Tomas Kirchhausen1,3 e-mail: kirchhausen@crystal.harvard.edu

Correspondence to: Matthew D Shair2,3 e-mail: shair@chemistry.harvard.edu

* note made in HTML and Fig 3a; PDF appended; corrected online date added to PDF

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