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Science 302 (5651): 1775-1779

Copyright © 2003 by the American Association for the Advancement of Science

Regulation of Cell Polarity and Protrusion Formation by Targeting RhoA for Degradation

Hong-Rui Wang,*,1 Yue Zhang,*,1 Barish Ozdamar,1,2 Abiodun A. Ogunjimi,1 Evguenia Alexandrova,3 Gerald H. Thomsen,3 Jeffrey L. Wrana1,2{dagger}

Abstract: The Rho family of small guanosine triphosphatases regulates actin cytoskeleton dynamics that underlie cellular functions such as cell shape changes, migration, and polarity. We found that Smurf1, a HECT domain E3 ubiquitin ligase, regulated cell polarity and protrusive activity and was required to maintain the transformed morphology and motility of a tumor cell. Atypical protein kinase C zeta (PKC{zeta}), an effector of the Cdc42/Rac1-PAR6 polarity complex, recruited Smurf1 to cellular protrusions, where it controlled the local level of RhoA. Smurf1 thus links the polarity complex to degradation of RhoA in lamellipodia and filopodia to prevent RhoA signaling during dynamic membrane movements.

1 Program in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto M56 1x5, Canada.
2 Department of Medical Genetics and Microbiology, University of Toronto, Toronto M5S 1A8, Canada.
3 Department of Biochemistry and Cell Biology, Center for Developmental Genetics, CMM 348, Stony Brook University, Stony Brook, NY 11794–5215, USA.

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* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: wrana{at}

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Z. Jia, L. Barbier, H. Stuart, M. Amraei, S. Pelech, J. W. Dennis, P. Metalnikov, P. O'Donnell, and I. R. Nabi (2005)
J. Biol. Chem. 280, 30564-30573
   Abstract »    Full Text »    PDF »
Protein Kinase A Gating of a Pseudopodial-located RhoA/ROCK/p38/NHE1 Signal Module Regulates Invasion in Breast Cancer Cell Lines.
R. A. Cardone, A. Bagorda, A. Bellizzi, G. Busco, L. Guerra, A. Paradiso, V. Casavola, M. Zaccolo, and S. J. Reshkin (2005)
Mol. Biol. Cell 16, 3117-3127
   Abstract »    Full Text »    PDF »
Degradation of the Tumor Suppressor Smad4 by WW and HECT Domain Ubiquitin Ligases.
A. Moren, T. Imamura, K. Miyazono, C.-H. Heldin, and A. Moustakas (2005)
J. Biol. Chem. 280, 22115-22123
   Abstract »    Full Text »    PDF »
Phosphorylation of Serine 188 Protects RhoA from Ubiquitin/Proteasome-Mediated Degradation in Vascular Smooth Muscle Cells.
M. Rolli-Derkinderen, V. Sauzeau, L. Boyer, E. Lemichez, C. Baron, D. Henrion, G. Loirand, and P. Pacaud (2005)
Circ. Res. 96, 1152-1160
   Abstract »    Full Text »    PDF »
Raf-1 regulates Rho signaling and cell migration.
K. Ehrenreiter, D. Piazzolla, V. Velamoor, I. Sobczak, J. V. Small, J. Takeda, T. Leung, and M. Baccarini (2005)
J. Cell Biol. 168, 955-964
   Abstract »    Full Text »    PDF »
Regulation of the Polarity Protein Par6 by TGF{beta} Receptors Controls Epithelial Cell Plasticity.
B. Ozdamar, R. Bose, M. Barrios-Rodiles, H.-R. Wang, Y. Zhang, and J. L. Wrana (2005)
Science 307, 1603-1609
   Abstract »    Full Text »    PDF »
Protein interaction mapping: A Drosophila case study.
E. Formstecher, S. Aresta, V. Collura, A. Hamburger, A. Meil, A. Trehin, C. Reverdy, V. Betin, S. Maire, C. Brun, et al. (2005)
Genome Res. 15, 376-384
   Abstract »    Full Text »    PDF »
Cdc42 Mediates Nucleus Movement and MTOC Polarization in Swiss 3T3 Fibroblasts under Mechanical Shear Stress.
J. S.H. Lee, M. I. Chang, Y. Tseng, and D. Wirtz (2005)
Mol. Biol. Cell 16, 871-880
   Abstract »    Full Text »    PDF »
R-Ras Controls Membrane Protrusion and Cell Migration through the Spatial Regulation of Rac and Rho.
M. A. Wozniak, L. Kwong, D. Chodniewicz, R. L. Klemke, and P. J. Keely (2005)
Mol. Biol. Cell 16, 84-96
   Abstract »    Full Text »    PDF »
GEFT, A Rho Family Guanine Nucleotide Exchange Factor, Regulates Neurite Outgrowth and Dendritic Spine Formation.
B. Bryan, V. Kumar, L. J. Stafford, Y. Cai, G. Wu, and M. Liu (2004)
J. Biol. Chem. 279, 45824-45832
   Abstract »    Full Text »    PDF »
The Rac1 C-terminal Polybasic Region Regulates the Nuclear Localization and Protein Degradation of Rac1.
C. C. Lanning, J. L. Daddona, R. Ruiz-Velasco, S. H. Shafer, and C. L. Williams (2004)
J. Biol. Chem. 279, 44197-44210
   Abstract »    Full Text »    PDF »
Epithelial cell spreading induced by hepatocyte growth factor influences paxillin protein synthesis and posttranslational modification.
A. M. Hopkins, M. Bruewer, G. T. Brown, A. A. Pineda, J. J. Ha, L. M. Winfree, S. V. Walsh, B. A. Babbin, and A. Nusrat (2004)
Am J Physiol Gastrointest Liver Physiol 287, G886-G898
   Abstract »    Full Text »    PDF »
Targeted Deletion of Protein Kinase C {lambda} Reveals a Distribution of Functions between the Two Atypical Protein Kinase C Isoforms.
R. S. Soloff, C. Katayama, M. Y. Lin, J. R. Feramisco, and S. M. Hedrick (2004)
J. Immunol. 173, 3250-3260
   Abstract »    Full Text »    PDF »
CELL BIOLOGY: Smurfing at the Leading Edge.
A. B. Jaffe and A. Hall (2003)
Science 302, 1690-1691
   Abstract »    Full Text »    PDF »

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