Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

J. Cell Biol. 151 (2): 249-262

Copyright © 2000 by the Rockefeller University Press.


Original Article

Role of the Pi3k Regulatory Subunit in the Control of Actin Organization and Cell Migration

Concepción Jiméneza, Rosario Armas Portelab, Mario Melladoa, Jose Miguel Rodríguez-Fradea, John Collardc, Antonio Serranoa, Carlos Martínez-Aa, Jesus Avilab, , and Ana C. Carreraa

a Department of Immunology and Oncology, Centro Nacional de Biotecnología,
b Centro de Biología Molecular, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Cantoblanco, Madrid E-28049, Spain
c The Netherlands Cancer Institute, Division of Cell Biology, 1066 CX, Amsterdam, The Netherlands
Department of Immunology and Oncology, Centro Nacional de Biotecnología, Carretera de Colmenar Km 16, Cantoblanco, Madrid E-28049, Spain.34-91-372-049334-91-585-4849

Abstract: Cell migration represents an important cellular response that utilizes cytoskeletal reorganization as its driving force. Here, we describe a new signaling cascade linking PDGF receptor stimulation to actin rearrangements and cell migration. We demonstrate that PDGF activates Cdc42 and its downstream effector N-WASP to mediate filopodia formation, actin stress fiber disassembly, and a reduction in focal adhesion complexes. Induction of the Cdc42 pathway is independent of phosphoinositide 3-kinase (PI3K) enzymatic activity, but it is dependent on the p85{alpha} regulatory subunit of PI3K. Finally, data are provided showing that activation of this pathway is required for PDGF-induced cell migration on collagen. These observations show the essential role of the PI3K regulatory subunit p85{alpha} in controlling PDGF receptor–induced cytoskeletal changes and cell migration, illustrating a novel signaling pathway that links receptor stimulation at the cell membrane with actin dynamics.

Key Words: N-WASP • Cdc42 • PDGF • phosphatidylinositol 3-kinase • actin cytoskeleton



Abbreviations used in this paper: Ab, antibody; DN, dominant negative; ECM, extracellular matrix; F-actin, filamentous actin; GEF, guanine nucleotide exchange factors; N-WASP, N-Wiskott-Aldrich Syndrome family protein; LPA, lysophosphatidic acid; PDGF, platelet-derived growth factor; PDGF-R, PDGF receptor; PI3K, phosphoinositide 3-kinase.


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
The Structural Basis of PI3K Cancer Mutations: From Mechanism to Therapy.
S. Liu, S. Knapp, and A. A. Ahmed (2014)
Cancer Res. 74, 641-646
   Abstract »    Full Text »    PDF »
The Prognostic Significance of Eukaryotic Elongation Factor 1 Alpha-2 in Non-Small Cell Lung Cancer.
M. KAWAMURA, C. ENDO, A. SAKURADA, F. HOSHI, H. NOTSUDA, and T. KONDO (2014)
Anticancer Res 34, 651-658
   Abstract »    Full Text »    PDF »
Cbl ubiquitination of p85 is essential for Epo-induced EpoR endocytosis.
G. B. Bulut, R. Sulahian, H. Yao, and L. J.-s. Huang (2013)
Blood 122, 3964-3972
   Abstract »    Full Text »    PDF »
Inhibition of PI3K binding to activators by serine phosphorylation of PI3K regulatory subunit p85{alpha} Src homology-2 domains.
J. Y. Lee, Y.-H. Chiu, J. Asara, and L. C. Cantley (2011)
PNAS 108, 14157-14162
   Abstract »    Full Text »    PDF »
Mesenchymal stem cell migration is regulated by fibronectin through {alpha}5{beta}1-integrin-mediated activation of PDGFR-{beta} and potentiation of growth factor signals.
J. Veevers-Lowe, S. G. Ball, A. Shuttleworth, and C. M. Kielty (2011)
J. Cell Sci. 124, 1288-1300
   Abstract »    Full Text »    PDF »
Myosin II directly binds and inhibits Dbl family guanine nucleotide exchange factors: a possible link to Rho family GTPases.
C.-S. Lee, C.-K. Choi, E.-Y. Shin, M. A. Schwartz, and E.-G. Kim (2010)
J. Cell Biol. 190, 663-674
   Abstract »    Full Text »    PDF »
The Sodium-Hydrogen Exchanger NHE1 Is an Akt Substrate Necessary for Actin Filament Reorganization by Growth Factors.
M. E. Meima, B. A. Webb, H. E. Witkowska, and D. L. Barber (2009)
J. Biol. Chem. 284, 26666-26675
   Abstract »    Full Text »    PDF »
Biological properties of potent inhibitors of class I phosphatidylinositide 3-kinases: from PI-103 through PI-540, PI-620 to the oral agent GDC-0941.
F. I. Raynaud, S. A. Eccles, S. Patel, S. Alix, G. Box, I. Chuckowree, A. Folkes, S. Gowan, A. De Haven Brandon, F. Di Stefano, et al. (2009)
Mol. Cancer Ther. 8, 1725-1738
   Abstract »    Full Text »    PDF »
Ligand-induced EpoR internalization is mediated by JAK2 and p85 and is impaired by mutations responsible for primary familial and congenital polycythemia.
R. Sulahian, O. Cleaver, and L. J.-s. Huang (2009)
Blood 113, 5287-5297
   Abstract »    Full Text »    PDF »
BMP2 induction of actin cytoskeleton reorganization and cell migration requires PI3-kinase and Cdc42 activity.
C. Gamell, N. Osses, R. Bartrons, T. Ruckle, M. Camps, J. L. Rosa, and F. Ventura (2008)
J. Cell Sci. 121, 3960-3970
   Abstract »    Full Text »    PDF »
Caspase-8 Interacts with the p85 Subunit of Phosphatidylinositol 3-Kinase to Regulate Cell Adhesion and Motility.
J. Senft, B. Helfer, and S. M. Frisch (2007)
Cancer Res. 67, 11505-11509
   Abstract »    Full Text »    PDF »
The Phosphorylation of Myosin II at the Ser1 and Ser2 Is Critical for Normal Platelet-derived Growth Factor induced Reorganization of Myosin Filaments.
S. Komatsu and M. Ikebe (2007)
Mol. Biol. Cell 18, 5081-5090
   Abstract »    Full Text »    PDF »
Phosphoinositide 3 kinase {gamma} participates in T cell receptor induced T cell activation.
I. Alcazar, M. Marques, A. Kumar, E. Hirsch, M. Wymann, A. C. Carrera, and D. F. Barber (2007)
J. Exp. Med. 204, 2977-2987
   Abstract »    Full Text »    PDF »
Positive feedback between Cdc42 activity and H+ efflux by the Na-H exchanger NHE1 for polarity of migrating cells.
C. Frantz, A. Karydis, P. Nalbant, K. M. Hahn, and D. L. Barber (2007)
J. Cell Biol. 179, 403-410
   Abstract »    Full Text »    PDF »
Class IA Phosphoinositide 3-Kinase Modulates Basal Lymphocyte Motility in the Lymph Node.
M. P. Matheu, J. A. Deane, I. Parker, D. A. Fruman, and M. D. Cahalan (2007)
J. Immunol. 179, 2261-2269
   Abstract »    Full Text »    PDF »
Pharmacologic Characterization of a Potent Inhibitor of Class I Phosphatidylinositide 3-Kinases.
F. I. Raynaud, S. Eccles, P. A. Clarke, A. Hayes, B. Nutley, S. Alix, A. Henley, F. Di-Stefano, Z. Ahmad, S. Guillard, et al. (2007)
Cancer Res. 67, 5840-5850
   Abstract »    Full Text »    PDF »
The p85{alpha} Regulatory Subunit of Phosphoinositide 3-Kinase Potentiates c-Jun N-Terminal Kinase-Mediated Insulin Resistance.
C. M. Taniguchi, J. O. Aleman, K. Ueki, J. Luo, T. Asano, H. Kaneto, G. Stephanopoulos, L. C. Cantley, and C. R. Kahn (2007)
Mol. Cell. Biol. 27, 2830-2840
   Abstract »    Full Text »    PDF »
PTEN Regulation, a Novel Function for the p85 Subunit of Phosphoinositide 3-Kinase.
D. F. Barber, M. Alvarado-Kristensson, A. Gonzalez-Garcia, R. Pulido, and A. C. Carrera (2006)
Sci. STKE 2006, pe49
   Abstract »    Full Text »    PDF »
A PI3K activity-independent function of p85 regulatory subunit in control of mammalian cytokinesis.
Z. Garcia, V. Silio, M. Marques, I. Cortes, A. Kumar, C. Hernandez, A. I. Checa, A. Serrano, and A. C. Carrera (2006)
EMBO J. 25, 4740-4751
   Abstract »    Full Text »    PDF »
Regulation of epidermal homeostasis and repair by phosphoinositide 3-kinase.
S. Pankow, C. Bamberger, A. Klippel, and S. Werner (2006)
J. Cell Sci. 119, 4033-4046
   Abstract »    Full Text »    PDF »
RacG Regulates Morphology, Phagocytosis, and Chemotaxis.
B. P. Somesh, G. Vlahou, M. Iijima, R. H. Insall, P. Devreotes, and F. Rivero (2006)
Eukaryot. Cell 5, 1648-1663
   Abstract »    Full Text »    PDF »
Cross-talk among Rho GTPases Acting Downstream of PI 3-Kinase Induces Mesenchymal Transformation of Corneal Endothelial Cells Mediated by FGF-2..
J. G. Lee and E. P. Kay (2006)
Invest. Ophthalmol. Vis. Sci. 47, 2358-2368
   Abstract »    Full Text »    PDF »
PDGF regulates the actin cytoskeleton through hnRNP-K-mediated activation of the ubiquitin E3-ligase MIR.
K. Nagano, B. C. Bornhauser, G. Warnasuriya, A. Entwistle, R. Cramer, D. Lindholm, and S. Naaby-Hansen (2006)
EMBO J. 25, 1871-1882
   Abstract »    Full Text »    PDF »
FGF-2-Induced Wound Healing in Corneal Endothelial Cells Requires Cdc42 Activation and Rho Inactivation through the Phosphatidylinositol 3-Kinase Pathway..
J. G. Lee and E. P. Kay (2006)
Invest. Ophthalmol. Vis. Sci. 47, 1376-1386
   Abstract »    Full Text »    PDF »
Phosphoinositide 3-kinase controls early and late events in mammalian cell division.
Z. Garcia, A. Kumar, M. Marques, I. Cortes, and A. C. Carrera (2006)
EMBO J. 25, 655-661
   Abstract »    Full Text »    PDF »
Divergent Roles of c-Src in Controlling Platelet-derived Growth Factor-dependent Signaling in Fibroblasts.
K. Shah and F. Vincent (2005)
Mol. Biol. Cell 16, 5418-5432
   Abstract »    Full Text »    PDF »
Dysadherin Expression Facilitates Cell Motility and Metastatic Potential of Human Pancreatic Cancer Cells.
T. Shimamura, J. Yasuda, Y. Ino, M. Gotoh, A. Tsuchiya, A. Nakajima, M. Sakamoto, Y. Kanai, and S. Hirohashi (2004)
Cancer Res. 64, 6989-6995
   Abstract »    Full Text »    PDF »
v-Src accelerates spontaneous motility via phosphoinositide 3-kinase, phospholipase C and phospholipase D, but abrogates chemotaxis in Rat-1 and MDCK cells.
A. Platek, M. Mettlen, I. Camby, R. Kiss, M. Amyere, and P. J. Courtoy (2004)
J. Cell Sci. 117, 4849-4861
   Abstract »    Full Text »    PDF »
FGF-2 Induced by Interleukin-1{beta} through the Action of Phosphatidylinositol 3-Kinase Mediates Endothelial Mesenchymal Transformation in Corneal Endothelial Cells.
H. T. Lee, J. G. Lee, M. Na, and E. P. Kay (2004)
J. Biol. Chem. 279, 32325-32332
   Abstract »    Full Text »    PDF »
Aggretin, a snake venom-derived endothelial integrin {alpha}2{beta}1 agonist, induces angiogenesis via expression of vascular endothelial growth factor.
C.-H. Chung, W.-B. Wu, and T.-F. Huang (2004)
Blood 103, 2105-2113
   Abstract »    Full Text »    PDF »
Control of Cyclin G2 mRNA Expression by Forkhead Transcription Factors: Novel Mechanism for Cell Cycle Control by Phosphoinositide 3-Kinase and Forkhead.
L. Martinez-Gac, M. Marques, Z. Garcia, M. R. Campanero, and A. C. Carrera (2004)
Mol. Cell. Biol. 24, 2181-2189
   Abstract »    Full Text »    PDF »
RhoA activation promotes transendothelial migration of monocytes via ROCK.
H. Honing, T. K. van den Berg, S. M. A. van der Pol, C. D. Dijkstra, R. A. van der Kammen, J. G. Collard, and H. E. de Vries (2004)
J. Leukoc. Biol. 75, 523-528
   Abstract »    Full Text »    PDF »
PI3K induced actin filament remodeling through Akt and p70S6K1: implication of essential role in cell migration.
Y. Qian, L. Corum, Q. Meng, J. Blenis, J. Z. Zheng, X. Shi, D. C. Flynn, and B.-H. Jiang (2004)
Am J Physiol Cell Physiol 286, C153-C163
   Abstract »    Full Text »    PDF »
IL-12 p40 Homodimer-Dependent Macrophage Chemotaxis and Respiratory Viral Inflammation Are Mediated through IL-12 Receptor {beta}1.
T. D. Russell, Q. Yan, G. Fan, A. P. Khalifah, D. K. Bishop, S. L. Brody, and M. J. Walter (2003)
J. Immunol. 171, 6866-6874
   Abstract »    Full Text »    PDF »
{beta}-casein-derived peptides, produced by bacteria, stimulate cancer cell invasion and motility.
M. J. Oliveira, J. Van Damme, T. Lauwaet, V. De Corte, G. De Bruyne, G. Verschraegen, M. Vaneechoutte, M. Goethals, M. R. Ahmadian, O. Muller, et al. (2003)
EMBO J. 22, 6161-6173
   Abstract »    Full Text »    PDF »
Tie-2-dependent activation of RhoA and Rac1 participates in endothelial cell motility triggered by angiopoietin-1.
I. Cascone, E. Audero, E. Giraudo, L. Napione, F. Maniero, M. R. Philips, J. G. Collard, G. Serini, and F. Bussolino (2003)
Blood 102, 2482-2490
   Abstract »    Full Text »    PDF »
Phosphoinositide 3-Kinase Activation Regulates Cell Division Time by Coordinated Control of Cell Mass and Cell Cycle Progression Rate.
B. Alvarez, E. Garrido, J. A. Garcia-Sanz, and A. C. Carrera (2003)
J. Biol. Chem. 278, 26466-26473
   Abstract »    Full Text »    PDF »
WIP participates in actin reorganization and ruffle formation induced by PDGF.
I. M. Anton, S. P. Saville, M. J. Byrne, C. Curcio, N. Ramesh, J. H. Hartwig, and R. S. Geha (2003)
J. Cell Sci. 116, 2443-2451
   Abstract »    Full Text »    PDF »
Genetic evidence for convergence of c-Kit- and {alpha}4 integrin-mediated signals on class IA PI-3kinase and the Rac pathway in regulating integrin-directed migration in mast cells.
B. L. Tan, M. N. Yazicioglu, D. Ingram, J. McCarthy, J. Borneo, D. A. Williams, and R. Kapur (2003)
Blood 101, 4725-4732
   Abstract »    Full Text »    PDF »
PTEN is essential for cell migration but not for fate determination and tumourigenesis in the cerebellum.
S. Marino, P. Krimpenfort, C. Leung, H. A. G. M. van der Korput, J. Trapman, I. Camenisch, A. Berns, and S. Brandner (2003)
Development 129, 3513-3522
   Abstract »    Full Text »    PDF »
Embryonic Testis Cord Formation and Mesonephric Cell Migration Requires the Phosphotidylinositol 3-Kinase Signaling Pathway.
M. Uzumcu, S. D. Westfall, K. A. Dirks, and M. K. Skinner (2002)
Biol Reprod 67, 1927-1935
   Abstract »    Full Text »    PDF »
HIV Nef Inhibits T Cell Migration.
E. Y. Choe, E. S. Schoenberger, J. E. Groopman, and I.-W. Park (2002)
J. Biol. Chem. 277, 46079-46084
   Abstract »    Full Text »    PDF »
Activation of Rac-1, Rac-2, and Cdc42 by hemopoietic growth factors or cross-linking of the B-lymphocyte receptor for antigen.
B. Grill and J. W. Schrader (2002)
Blood 100, 3183-3192
   Abstract »    Full Text »    PDF »
Chlamydia trachomatis Induces Remodeling of the Actin Cytoskeleton during Attachment and Entry into HeLa Cells.
R. A. Carabeo, S. S. Grieshaber, E. Fischer, and T. Hackstadt (2002)
Infect. Immun. 70, 3793-3803
   Abstract »    Full Text »    PDF »
N-WASP activation by a {beta}1-integrin-dependent mechanism supports PI3K-independent chemotaxis stimulated by urokinase-type plasminogen activator.
J. Sturge, J. Hamelin, and G. E. Jones (2002)
J. Cell Sci. 115, 699-711
   Abstract »    Full Text »    PDF »
Flt-1-mediated Down-regulation of Endothelial Cell Proliferation through Pertussis Toxin-sensitive G Proteins, beta gamma Subunits, Small GTPase CDC42, and Partly by Rac-1.
H. Zeng, D. Zhao, and D. Mukhopadhyay (2002)
J. Biol. Chem. 277, 4003-4009
   Abstract »    Full Text »    PDF »
The Rat Homologue of Wiskott-Aldrich Syndrome Protein (WASP)-interacting Protein (WIP) Associates with Actin Filaments, Recruits N-WASP from the Nucleus, and Mediates Mobilization of Actin from Stress Fibers in Favor of Filopodia Formation.
S. Vetterkind, H. Miki, T. Takenawa, I. Klawitz, K.-H. Scheidtmann, and U. Preuss (2002)
J. Biol. Chem. 277, 87-95
   Abstract »    Full Text »    PDF »
Platelet-derived Growth Factor Inhibits Smooth Muscle Cell Adhesion to Fibronectin by ERK-dependent and ERK-independent Pathways.
E. Berrou and M. Bryckaert (2001)
J. Biol. Chem. 276, 39303-39309
   Abstract »    Full Text »    PDF »
New Responsibilities for the PI3K Regulatory Subunit p85{alpha}.
K. Okkenhaug and B. Vanhaesebroeck (2001)
Sci. STKE 2001, pe1
   Abstract »    Full Text »    PDF »
Expression of Functional Chemokine Receptors CXCR3 and CXCR4 on Human Melanoma Cells.
M. M. Robledo, R. A. Bartolome, N. Longo, J. M. Rodriguez-Frade, M. Mellado, I. Longo, G. N. P. van Muijen, P. Sanchez-Mateos, and J. Teixido (2001)
J. Biol. Chem. 276, 45098-45105
   Abstract »    Full Text »    PDF »
Phosphatidylinositol 3-Kinase p85 Adaptor Function in T-cells. CO-STIMULATION AND REGULATION OF CYTOKINE TRANSCRIPTION INDEPENDENT OF ASSOCIATED p110.
H. Kang, H. Schneider, and C. E. Rudd (2002)
J. Biol. Chem. 277, 912-921
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882