QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

Vol. 18, Issue 8, 2935-2948, August 2007

This Article Full Text Full Text (PDF) Supplemental Material All Versions of this Article: E06-11-1031v1 18/8/2935    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Prag, S. Articles by Ng, T. Search for Related Content PubMed PubMed Citation Articles by Prag, S. Articles by Ng, T.

Activated Ezrin Promotes Cell Migration through Recruitment of the GEF Dbl to Lipid Rafts and Preferential Downstream Activation of Cdc42

Soren Prag^*,,,, Maddy Parsons^,, Melanie D. Keppler^*,, Simon M. Ameer-Beg^*,, Paul Barber^||, James Hunt^,¶, Andrew J. Beavil^,¶, Rosy Calvert^,¶, Monique Arpin^#, Borivoj Vojnovic^||, and Tony Ng^*,

*Richard Dimbleby Department of Cancer Research, Randall Division of Cell and Molecular Biophysics, and ^¶Division of Asthma, Allergy, and Lung Biology, King's College London, Guy's Medical School Campus, London SE1 1UL, United Kingdom; ^||Gray Cancer Institute, Oxford University, Mount Vernon Hospital, Northwood, Middlesex, HA6 2JR, United Kingdom; and ^#Laboratoire de Morphogenese et Signalisation Cellulaires, Institut Curie, 75248 Paris Cedex 05, France

Submitted November 21, 2006; Revised May 18, 2007; Accepted May 23, 2007
Monitoring Editor: Paul Forscher

Establishment of polarized cell morphology is a critical factor for migration and requires precise spatial and temporal activation of the Rho GTPases. Here, we describe a novel role of the actin-binding ezrin/radixin/moesin (ERM)-protein ezrin to be involved in recruiting Cdc42, but not Rac1, to lipid raft microdomains, as well as the subsequent activation of this Rho GTPase and the downstream effector p21-activated kinase (PAK)1, as shown by fluorescence lifetime imaging microscopy. The establishment of a leading plasma membrane and the polarized morphology necessary for random migration are also dependent on ERM function and Cdc42 in motile breast carcinoma cells. Mechanistically, we show that the recruitment of the ERM-interacting Rho/Cdc42-specific guanine nucleotide exchange factor Dbl to the plasma membrane and to lipid raft microdomains requires the phosphorylated, active conformer of ezrin, which serves to tether the plasma membrane or its subdomains to the cytoskeleton. Together these data suggest a mechanism whereby precise spatial guanine nucleotide exchange of Cdc42 by Dbl is dependent on functional ERM proteins and is important for directional cell migration.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

These authors contributed equally to this work.

Present address: Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, Portugal.

Address correspondence to: Soren Prag (sprag{at}fm.ul.pt) or Tony Ng (tony.ng{at}kcl.ac.uk).

Abbreviations used: C-ERMAD, COOH-terminal ERM-associated domain; CTxB, cholera toxin subunit B; ERM, ezrin/radixin/moesin; FERM, band 4.1, ezrin, radixin, moesin; FLIM, fluorescent lifetime imagining measurements; FRET, Förster resonance energy transfer; GEF, guanine nucleotide exchange factor; N-ERMAD, NH₂-terminal ERM-associated domain

This article has been cited by other articles:

				A. Estecha, L. Sanchez-Martin, A. Puig-Kroger, R. A. Bartolome, J. Teixido, R. Samaniego, and P. Sanchez-Mateos Moesin orchestrates cortical polarity of melanoma tumour cells to initiate 3D invasion J. Cell Sci., October 1, 2009; 122(19): 3492 - 3501. [Abstract] [Full Text] [PDF]

				K. Makrogianneli, L. M. Carlin, M. D. Keppler, D. R. Matthews, E. Ofo, A. Coolen, S. M. Ameer-Beg, P. R. Barber, B. Vojnovic, and T. Ng Integrating Receptor Signal Inputs That Influence Small Rho GTPase Activation Dynamics at the Immunological Synapse Mol. Cell. Biol., June 1, 2009; 29(11): 2997 - 3006. [Abstract] [Full Text] [PDF]

				D. J. Killock, M. Parsons, M. Zarrouk, S. M. Ameer-Beg, A. J. Ridley, D. O. Haskard, M. Zvelebil, and A. Ivetic In Vitro and in Vivo Characterization of Molecular Interactions between Calmodulin, Ezrin/Radixin/Moesin, and L-selectin J. Biol. Chem., March 27, 2009; 284(13): 8833 - 8845. [Abstract] [Full Text] [PDF]

				A. A. Paulucci-Holthauzen, L. A. Vergara, L. J. Bellot, D. Canton, J. D. Scott, and K. L. O'Connor Spatial Distribution of Protein Kinase A Activity during Cell Migration Is Mediated by A-kinase Anchoring Protein AKAP Lbc J. Biol. Chem., February 27, 2009; 284(9): 5956 - 5967. [Abstract] [Full Text] [PDF]

				P.R Barber, S.M Ameer-Beg, J Gilbey, L.M Carlin, M Keppler, T.C Ng, and B Vojnovic Multiphoton time-domain fluorescence lifetime imaging microscopy: practical application to protein-protein interactions using global analysis J R Soc Interface, February 6, 2009; 6(Suppl_1): S93 - S105. [Abstract] [Full Text] [PDF]

				E. K. Hoffmann, I. H. Lambert, and S. F. Pedersen Physiology of Cell Volume Regulation in Vertebrates Physiol Rev, January 1, 2009; 89(1): 193 - 277. [Abstract] [Full Text] [PDF]

				M. Parsons and J. C. Adams Rac regulates the interaction of fascin with protein kinase C in cell migration J. Cell Sci., September 1, 2008; 121(17): 2805 - 2813. [Abstract] [Full Text] [PDF]

				J. Haedicke, K. de los Santos, S. P. Goff, and M. H. Naghavi The Ezrin-Radixin-Moesin Family Member Ezrin Regulates Stable Microtubule Formation and Retroviral Infection J. Virol., May 1, 2008; 82(9): 4665 - 4670. [Abstract] [Full Text] [PDF]

				Y. H. Zeidan, R. W. Jenkins, and Y. A. Hannun Remodeling of cellular cytoskeleton by the acid sphingomyelinase/ceramide pathway J. Cell Biol., April 21, 2008; 181(2): 335 - 350. [Abstract] [Full Text] [PDF]

				M. Parsons, A. J. Messent, J. D. Humphries, N. O. Deakin, and M. J. Humphries Quantification of integrin receptor agonism by fluorescence lifetime imaging J. Cell Sci., February 1, 2008; 121(3): 265 - 271. [Abstract] [Full Text] [PDF]

				C. Frantz, A. Karydis, P. Nalbant, K. M. Hahn, and D. L. Barber Positive feedback between Cdc42 activity and H+ efflux by the Na-H exchanger NHE1 for polarity of migrating cells J. Cell Biol., November 5, 2007; 179(3): 403 - 410. [Abstract] [Full Text] [PDF]