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Science 303 (5659): 839-842

Copyright © 2004 by the American Association for the Advancement of Science

Integrins Regulate Rac Targeting by Internalization of Membrane Domains

Miguel A. del Pozo,1,2,3* Nazilla B. Alderson,1,2 William B. Kiosses,1 Hui-Hsien Chiang,1 Richard G. W. Anderson,4 Martin A. Schwartz1,5

Abstract: Translocation of the small GTP-binding protein Rac1 to the cell plasma membrane is essential for activating downstream effectors and requires integrin-mediated adhesion of cells to extracellular matrix. We report that active Rac1 binds preferentially to low-density, cholesterol-rich membranes, and specificity is determined at least in part by membrane lipids. Cell detachment triggered internalization of plasma membrane cholesterol and lipid raft markers. Preventing internalization maintained Rac1 membrane targeting and effector activation in nonadherent cells. Regulation of lipid rafts by integrin signals may regulate the location of membrane domains such as lipid rafts and thereby control domain-specific signaling events in anchorage-dependent cells.

1 Department of Cell Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
2 Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
3 Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.
4 Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA.
5 Departments of Microbiology and Biomedical Engineering, Mellon Prostate Cancer Research Institute and Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908, USA.

* To whom correspondence should be addressed. E-mail: mdelpozo{at}scripps.edu


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Syndecan-4-dependent Rac1 regulation determines directional migration in response to the extracellular matrix.
M. D. Bass, K. A. Roach, M. R. Morgan, Z. Mostafavi-Pour, T. Schoen, T. Muramatsu, U. Mayer, C. Ballestrem, J. P. Spatz, and M. J. Humphries (2007)
J. Cell Biol. 177, 527-538
   Abstract »    Full Text »    PDF »
Integrin {alpha}1{beta}1 Controls Reactive Oxygen Species Synthesis by Negatively Regulating Epidermal Growth Factor Receptor-Mediated Rac Activation.
X. Chen, T. D. Abair, M. R. Ibanez, Y. Su, M. R. Frey, R. S. Dise, D. B. Polk, A. B. Singh, R. C. Harris, R. Zent, et al. (2007)
Mol. Cell. Biol. 27, 3313-3326
   Abstract »    Full Text »    PDF »
Ca2+-activated IK1 Channels Associate with Lipid Rafts upon Cell Swelling and Mediate Volume Recovery.
E. T. Barfod, A. L. Moore, M. W. Roe, and S. D. Lidofsky (2007)
J. Biol. Chem. 282, 8984-8993
   Abstract »    Full Text »    PDF »
Activation Status-Coupled Transient S Acylation Determines Membrane Partitioning of a Plant Rho-Related GTPase.
N. Sorek, L. Poraty, H. Sternberg, E. Bar, E. Lewinsohn, and S. Yalovsky (2007)
Mol. Cell. Biol. 27, 2144-2154
   Abstract »    Full Text »    PDF »
Cholesterol-dependent actin remodeling via RhoA and Rac1 activation by the Streptococcus pneumoniae toxin pneumolysin.
A. I. Iliev, J. R. Djannatian, R. Nau, T. J. Mitchell, and F. S. Wouters (2007)
PNAS 104, 2897-2902
   Abstract »    Full Text »    PDF »
Urokinase Receptors Are Required for {alpha}5beta1 Integrin-mediated Signaling in Tumor Cells.
Y. Wei, C.-H. Tang, Y. Kim, L. Robillard, F. Zhang, M. C. Kugler, and H. A. Chapman (2007)
J. Biol. Chem. 282, 3929-3939
   Abstract »    Full Text »    PDF »
The reduced GM-CSF priming of ROS production in granulocytes from patients with myelodysplasia is associated with an impaired lipid raft formation.
G. M. Fuhler, N. R. Blom, P. J. Coffer, A. L. Drayer, and E. Vellenga (2007)
J. Leukoc. Biol. 81, 449-457
   Abstract »    Full Text »    PDF »
Filamin links cell shape and cytoskeletal structure to Rho regulation by controlling accumulation of p190RhoGAP in lipid rafts.
A. Mammoto, S. Huang, and D. E. Ingber (2007)
J. Cell Sci. 120, 456-467
   Abstract »    Full Text »    PDF »
Role of EGF-induced tyrosine phosphorylation of reggie-1/flotillin-2 in cell spreading and signaling to the actin cytoskeleton.
C. Neumann-Giesen, I. Fernow, M. Amaddii, and R. Tikkanen (2007)
J. Cell Sci. 120, 395-406
   Abstract »    Full Text »    PDF »
FAK Potentiates Rac1 Activation and Localization to Matrix Adhesion Sites: A Role for betaPIX.
F. Chang, C. A. Lemmon, D. Park, and L. H. Romer (2007)
Mol. Biol. Cell 18, 253-264
   Abstract »    Full Text »    PDF »
Anisotropy of cell adhesive microenvironment governs cell internal organization and orientation of polarity.
M. Thery, V. Racine, M. Piel, A. Pepin, A. Dimitrov, Y. Chen, J.-B. Sibarita, and M. Bornens (2006)
PNAS 103, 19771-19776
   Abstract »    Full Text »    PDF »
Integrin-Linked Kinase Expression Is Elevated in Human Cardiac Hypertrophy and Induces Hypertrophy in Transgenic Mice.
H. Lu, P. W. M. Fedak, X. Dai, C. Du, Y.-Q. Zhou, M. Henkelman, P. S. Mongroo, A. Lau, H. Yamabi, A. Hinek, et al. (2006)
Circulation 114, 2271-2279
   Abstract »    Full Text »    PDF »
Atorvastatin Restores Lck Expression and Lipid Raft-Associated Signaling in T Cells from Patients with Systemic Lupus Erythematosus.
E. C. Jury, D. A. Isenberg, C. Mauri, and M. R. Ehrenstein (2006)
J. Immunol. 177, 7416-7422
   Abstract »    Full Text »    PDF »
Plitidepsin Cellular Binding and Rac1/JNK Pathway Activation Depend on Membrane Cholesterol Content.
Y. Suarez, L. Gonzalez-Santiago, N. Zarich, A. Davalos, J. F. Aranda, M. A. Alonso, M. A. Lasuncion, J. M. Rojas, and A. Munoz (2006)
Mol. Pharmacol. 70, 1654-1663
   Abstract »    Full Text »    PDF »
Caveolin-Dependent Angiotensin II Type 1 Receptor Signaling in Vascular Smooth Muscle.
M. Ushio-Fukai and R. W. Alexander (2006)
Hypertension 48, 797-803
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