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.


Logo for

PNAS 96 (24): 13813-13818

Copyright © 1999 by the National Academy of Sciences.

Inaugural Article


An Eph receptor regulates integrin activity through R-Ras

June X. Zou, Bingcheng Wang*, Matthew S. Kalo, Andreas H. Zisch{dagger}, Elena B. Pasquale, and Erkki Ruoslahti{ddagger}

Cancer Research Center, The Burnham Institute, La Jolla, CA 92037

Contributed by Erkki Ruoslahti

Accepted for publication September 17, 1999.

Abstract: The ability of integrins to mediate cell attachment to extracellular matrices and to blood proteins is regulated from inside the cell. Increased ligand-binding activity of integrins is critical for platelet aggregation upon blood clotting and for leukocyte extravasation to inflamed tissues. Decreased adhesion is thought to promote tumor cell invasion. R-Ras, a small intracellular GTPase, regulates the binding of integrins to their ligands outside the cell. Here we show that the Eph receptor tyrosine kinase, EphB2, can control integrin activity through R-Ras. Cells in which EphB2 is activated become poorly adherent to substrates coated with integrin ligands, and a tyrosine residue in the R-Ras effector domain is phosphorylated. The R-Ras phosphorylation and loss of cell adhesion are causally related, because forced expression of an R-Ras variant resistant to phosphorylation at the critical site made cells unresponsive to the anti-adhesive effect of EphB2. This is an unusual regulatory pathway among the small GTPases. Reduced adhesiveness induced through the Eph/R-Ras pathway may explain the repulsive effect of the Eph receptors in axonal pathfinding and may facilitate tumor cell invasion and angiogenesis.

* Present address: Rammelkamp Center for Research, Metro-Health Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH 44109.

{dagger} Present address: Department of Materials and Institute for Biomedical Engineering, ETH Zurich and the University of Zurich, Moussonstrasse 18, CH-8044 Zurich, Switzerland.

{ddagger} To whom reprint requests should be addressed at: The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037. E-mail: ruoslahti{at}

EphB2 activity plays a pivotal role in pediatric medulloblastoma cell adhesion and invasion.
A. H. Sikkema, W. F. A. den Dunnen, E. Hulleman, D. G. van Vuurden, G. Garcia-Manero, H. Yang, F. J. G. Scherpen, K. R. Kampen, E. W. Hoving, W. A. Kamps, et al. (2012)
Neuro Oncology 14, 1125-1135
   Abstract »    Full Text »    PDF »
Alendronate Affects Osteoblast Functions by Crosstalk through EphrinB1-EphB.
E. Shimizu, J. Tamasi, and N. C. Partridge (2012)
Journal of Dental Research 91, 268-274
   Abstract »    PDF »
A genome-wide RNAi screen in mouse embryonic stem cells identifies Mp1 as a key mediator of differentiation.
B. A. Westerman, A. K. Braat, N. Taub, M. Potman, J. H. A. Vissers, M. Blom, E. Verhoeven, H. Stoop, A. Gillis, A. Velds, et al. (2011)
J. Exp. Med. 208, 2675-2689
   Abstract »    Full Text »    PDF »
A Paradigm Shift in EPH Receptor Interaction: Biological Relevance of EPHB6 Interaction with EPHA2 and EPHB2 in Breast Carcinoma Cell Lines.
B. P. Fox and R. P. Kandpal (2011)
Cancer Genomics Proteomics 8, 185-193
   Abstract »    Full Text »    PDF »
EphB2-mediated interactions are essential for proper migration of T cell progenitors during fetal thymus colonization.
M. A. Stimamiglio, E. Jimenez, S. D. Silva-Barbosa, D. Alfaro, J. J. Garcia-Ceca, J. J. Munoz, T. Cejalvo, W. Savino, and A. Zapata (2010)
J. Leukoc. Biol. 88, 483-494
   Abstract »    Full Text »    PDF »
EphA1 interacts with integrin-linked kinase and regulates cell morphology and motility.
T. Yamazaki, J. Masuda, T. Omori, R. Usui, H. Akiyama, and Y. Maru (2009)
J. Cell Sci. 122, 243-255
   Abstract »    Full Text »    PDF »
The EphA2 Receptor and EphrinA1 Ligand in Solid Tumors: Function and Therapeutic Targeting.
J. Wykosky and W. Debinski (2008)
Mol. Cancer Res. 6, 1795-1806
   Abstract »    Full Text »    PDF »
Ephrin-B2-induced Cleavage of EphB2 Receptor Is Mediated by Matrix Metalloproteinases to Trigger Cell Repulsion.
K.-T. Lin, S. Sloniowski, D. W. Ethell, and I. M. Ethell (2008)
J. Biol. Chem. 283, 28969-28979
   Abstract »    Full Text »    PDF »
Eph/ephrin signaling: networks.
D. Arvanitis and A. Davy (2008)
Genes & Dev. 22, 416-429
   Abstract »    Full Text »    PDF »
Identification of Phosphotyrosine Binding Domain-Containing Proteins as Novel Downstream Targets of the EphA8 Signaling Function.
J. Shin, C. Gu, E. Park, and S. Park (2007)
Mol. Cell. Biol. 27, 8113-8126
   Abstract »    Full Text »    PDF »
The Synovial Sarcoma SYT-SSX2 Oncogene Remodels the Cytoskeleton through Activation of the Ephrin Pathway.
R. Barco, L. B. Hunt, A. L. Frump, C. B. Garcia, A. Benesh, R. L. Caldwell, and J. E. Eid (2007)
Mol. Biol. Cell 18, 4003-4012
   Abstract »    Full Text »    PDF »
Ena/VASP proteins mediate repulsion from ephrin ligands.
I. R. Evans, T. Renne, F. B. Gertler, and C. D. Nobes (2007)
J. Cell Sci. 120, 289-298
   Abstract »    Full Text »    PDF »
The EphB4 Receptor-tyrosine Kinase Promotes the Migration of Melanoma Cells through Rho-mediated Actin Cytoskeleton Reorganization.
N.-Y. Yang, E. B. Pasquale, L. B. Owen, and I. M. Ethell (2006)
J. Biol. Chem. 281, 32574-32586
   Abstract »    Full Text »    PDF »
Cyclic AMP-dependent and Epac-mediated Activation of R-Ras by G Protein-coupled Receptors Leads to Phospholipase D Stimulation.
M. L. De Jesus, M. B. Stope, P. A. O. Weernink, Y. Mahlke, C. Borgermann, V. N. Ananaba, C. Rimmbach, D. Rosskopf, M. C. Michel, K. H. Jakobs, et al. (2006)
J. Biol. Chem. 281, 21837-21847
   Abstract »    Full Text »    PDF »
Semaphorin 4D/Plexin-B1-mediated R-Ras GAP activity inhibits cell migration by regulating {beta}1 integrin activity.
I. Oinuma, H. Katoh, and M. Negishi (2006)
J. Cell Biol. 173, 601-613
   Abstract »    Full Text »    PDF »
EphA Receptors Inhibit Anti-CD3-Induced Apoptosis in Thymocytes.
A. Freywald, N. Sharfe, C. DE. Miller, C. Rashotte, and C. M. Roifman (2006)
J. Immunol. 176, 4066-4074
   Abstract »    Full Text »    PDF »
Eph receptors inactivate R-Ras through different mechanisms to achieve cell repulsion.
M. Dail, M. Richter, P. Godement, and E. B. Pasquale (2006)
J. Cell Sci. 119, 1244-1254
   Abstract »    Full Text »    PDF »
Trans-activation of EphA4 and FGF receptors mediated by direct interactions between their cytoplasmic domains.
H. Yokote, K. Fujita, X. Jing, T. Sawada, S. Liang, L. Yao, X. Yan, Y. Zhang, J. Schlessinger, and K. Sakaguchi (2005)
PNAS 102, 18866-18871
   Abstract »    Full Text »    PDF »
Vascular Development of the Brain Requires {beta}8 Integrin Expression in the Neuroepithelium.
J. M. Proctor, K. Zang, D. Wang, R. Wang, and L. F. Reichardt (2005)
J. Neurosci. 25, 9940-9948
   Abstract »    Full Text »    PDF »
EphB2 Expression across 138 Human Tumor Types in a Tissue Microarray: High Levels of Expression in Gastrointestinal Cancers.
A. Lugli, H. Spichtin, R. Maurer, M. Mirlacher, J. Kiefer, P. Huusko, D. Azorsa, L. Terracciano, G. Sauter, O.-P Kallioniemi, et al. (2005)
Clin. Cancer Res. 11, 6450-6458
   Abstract »    Full Text »    PDF »
Biphasic Functions of the Kinase-defective Ephb6 Receptor in Cell Adhesion and Migration.
H. Matsuoka, H. Obama, M. L. Kelly, T. Matsui, and M. Nakamoto (2005)
J. Biol. Chem. 280, 29355-29363
   Abstract »    Full Text »    PDF »
Eph kinases and ephrins support thrombus growth and stability by regulating integrin outside-in signaling in platelets.
N. Prevost, D. S. Woulfe, H. Jiang, T. J. Stalker, P. Marchese, Z. M. Ruggeri, and L. F. Brass (2005)
PNAS 102, 9820-9825
   Abstract »    Full Text »    PDF »
Adaptation of Sensory Neurons to Hyalectin and Decorin Proteoglycans.
M. L. Lemons, S. Barua, M. L. Abanto, W. Halfter, and M. L. Condic (2005)
J. Neurosci. 25, 4964-4973
   Abstract »    Full Text »    PDF »
Expression of Eph receptors and their ligands, ephrins, during lipopolysaccharide fever in rats.
A. I. Ivanov, A. A. Steiner, A. C. Scheck, and A. A. Romanovsky (2005)
Physiol Genomics 21, 152-160
   Abstract »    Full Text »    PDF »
Ephrin-A1 binding to CD4+ T lymphocytes stimulates migration and induces tyrosine phosphorylation of PYK2.
H.-C. Aasheim, J. Delabie, and E. F. Finne (2005)
Blood 105, 2869-2876
   Abstract »    Full Text »    PDF »
Inhibition of Integrin-mediated Cell Adhesion but Not Directional Cell Migration Requires Catalytic Activity of EphB3 Receptor Tyrosine Kinase: ROLE OF RHO FAMILY SMALL GTPases.
H. Miao, K. Strebhardt, E. B. Pasquale, T.-L. Shen, J.-L. Guan, and B. Wang (2005)
J. Biol. Chem. 280, 923-932
   Abstract »    Full Text »    PDF »
Selective ablation of {alpha}v integrins in the central nervous system leads to cerebral hemorrhage, seizures, axonal degeneration and premature death.
J. H. McCarty, A. Lacy-Hulbert, A. Charest, R. T. Bronson, D. Crowley, D. Housman, J. Savill, J. Roes, and R. O. Hynes (2005)
Development 132, 165-176
   Abstract »    Full Text »    PDF »
Common Cues in Vascular and Axon Guidance.
G. Serini and F. Bussolino (2004)
Physiology 19, 348-354
   Abstract »    Full Text »    PDF »
SHEP1 Function in Cell Migration Is Impaired by a Single Amino Acid Mutation That Disrupts Association with the Scaffolding Protein Cas but Not with Ras GTPases.
M. Dail, M. S. Kalo, J. A. Seddon, J.-F. Cote, K. Vuori, and E. B. Pasquale (2004)
J. Biol. Chem. 279, 41892-41902
   Abstract »    Full Text »    PDF »
Human RAS Superfamily Proteins and Related GTPases.
J. Colicelli (2004)
Sci. STKE 2004, re13
   Abstract »    Full Text »    PDF »
The Phosphorylation of EphB2 Receptor Regulates Migration and Invasion of Human Glioma Cells.
M. Nakada, J. A. Niska, H. Miyamori, W. S. McDonough, J. Wu, H. Sato, and M. E. Berens (2004)
Cancer Res. 64, 3179-3185
   Abstract »    Full Text »    PDF »
Interplay between EphB4 on tumor cells and vascular ephrin-B2 regulates tumor growth.
N. K. Noren, M. Lu, A. L. Freeman, M. Koolpe, and E. B. Pasquale (2004)
PNAS 101, 5583-5588
   Abstract »    Full Text »    PDF »
Newest findings on the oldest oncogene; how activated src does it.
M. C. Frame (2004)
J. Cell Sci. 117, 989-998
   Abstract »    Full Text »    PDF »
Signaling by ephrinB1 and Eph kinases in platelets promotes Rap1 activation, platelet adhesion, and aggregation via effector pathways that do not require phosphorylation of ephrinB1.
N. Prevost, D. S. Woulfe, M. Tognolini, T. Tanaka, W. Jian, R. R. Fortna, H. Jiang, and L. F. Brass (2004)
Blood 103, 1348-1355
   Abstract »    Full Text »    PDF »
Antiangiogenic and Antitumor Efficacy of EphA2 Receptor Antagonist.
P. Dobrzanski, K. Hunter, S. Jones-Bolin, H. Chang, C. Robinson, S. Pritchard, H. Zhao, and B. Ruggeri (2004)
Cancer Res. 64, 910-919
   Abstract »    Full Text »    PDF »
Human dendritic cells express neuronal Eph receptor tyrosine kinases: role of EphA2 in regulating adhesion to fibronectin.
B. de Saint-Vis, C. Bouchet, G. Gautier, J. Valladeau, C. Caux, and P. Garrone (2003)
Blood 102, 4431-4440
   Abstract »    Full Text »    PDF »
The C-terminal end of R-Ras contains a focal adhesion targeting signal.
J. Furuhjelm and J. Peranen (2003)
J. Cell Sci. 116, 3729-3738
   Abstract »    Full Text »    PDF »
Ephrin-B2 and EphB2 Regulation of Astrocyte-Meningeal Fibroblast Interactions in Response to Spinal Cord Lesions in Adult Rats.
L. Q. Bundesen, T. A. Scheel, B. S. Bregman, and L. F. Kromer (2003)
J. Neurosci. 23, 7789-7800
   Abstract »    Full Text »    PDF »
`Eph'ective signaling: forward, reverse and crosstalk.
K. K. Murai and E. B. Pasquale (2003)
J. Cell Sci. 116, 2823-2832
   Abstract »    Full Text »    PDF »
Ephrin-B1 Reverse Signaling Activates JNK through a Novel Mechanism That Is Independent of Tyrosine Phosphorylation.
Z. Xu, K.-O. Lai, H.-M. Zhou, S.-C. Lin, and N. Y. Ip (2003)
J. Biol. Chem. 278, 24767-24775
   Abstract »    Full Text »    PDF »
Forward EphB4 signaling in endothelial cells controls cellular repulsion and segregation from ephrinB2 positive cells.
T. Fuller, T. Korff, A. Kilian, G. Dandekar, and H. G. Augustin (2003)
J. Cell Sci. 116, 2461-2470
   Abstract »    Full Text »    PDF »
The EphB6 Receptor Inhibits JNK Activation in T Lymphocytes and Modulates T Cell Receptor-mediated Responses.
A. Freywald, N. Sharfe, C. Rashotte, T. Grunberger, and C. M. Roifman (2003)
J. Biol. Chem. 278, 10150-10156
   Abstract »    Full Text »    PDF »
EphB1 Associates with Grb7 and Regulates Cell Migration.
D. C. Han, T.-L. Shen, H. Miao, B. Wang, and J.-L. Guan (2002)
J. Biol. Chem. 277, 45655-45661
   Abstract »    Full Text »    PDF »
Ephrin-B ligands play a dual role in the control of neural crest cell migration.
A. Santiago and C. A. Erickson (2002)
Development 129, 3621-3632
   Abstract »    Full Text »    PDF »
Interactions between Eph kinases and ephrins provide a mechanism to support platelet aggregation once cell-to-cell contact has occurred.
N. Prevost, D. Woulfe, T. Tanaka, and L. F. Brass (2002)
PNAS 99, 9219-9224
   Abstract »    Full Text »    PDF »
The oligodendrocyte precursor mitogen PDGF stimulates proliferation by activation of {alpha}v{beta}3 integrins.
W. Baron, S. J. Shattil, and C. ffrench-Constant (2002)
EMBO J. 21, 1957-1966
   Abstract »    Full Text »    PDF »
Ephrin-A5 induces rounding, blebbing and de-adhesion of EphA3-expressing 293T and melanoma cells by CrkII and Rho-mediated signalling.
I. D. Lawrenson, S. H. Wimmer-Kleikamp, P. Lock, S. M. Schoenwaelder, M. Down, A. W. Boyd, P. F. Alewood, and M. Lackmann (2002)
J. Cell Sci. 115, 1059-1072
   Abstract »    Full Text »    PDF »
Signals from Eph and Ephrin Proteins: A Developmental Tool Kit.
A. W. Boyd and M. Lackmann (2001)
Sci. STKE 2001, re20
   Abstract »    Full Text »    PDF »
Downregulation of the Ras-Mitogen-Activated Protein Kinase Pathway by the EphB2 Receptor Tyrosine Kinase Is Required for Ephrin-Induced Neurite Retraction.
S. Elowe, S. J. Holland, S. Kulkarni, and T. Pawson (2001)
Mol. Cell. Biol. 21, 7429-7441
   Abstract »    Full Text »    PDF »
The EphA8 Receptor Regulates Integrin Activity through p110{gamma} Phosphatidylinositol-3 Kinase in a Tyrosine Kinase Activity-Independent Manner.
C. Gu and S. Park (2001)
Mol. Cell. Biol. 21, 4579-4597
   Abstract »    Full Text »    PDF »
An ephrin-A-dependent Signaling Pathway Controls Integrin Function and Is Linked to the Tyrosine Phosphorylation of a 120-kDa Protein.
J. Huai and U. Drescher (2001)
J. Biol. Chem. 276, 6689-6694
   Abstract »    Full Text »    PDF »
Crkl Enhances Leukemogenesis in BCR/ABL P190 Transgenic Mice.
B. Hemmeryckx, A. van Wijk, A. Reichert, V. Kaartinen, Ron de Jong, P. K. Pattengale, I. Gonzalez-Gomez, J. Groffen, and N. Heisterkamp (2001)
Cancer Res. 61, 1398-1405
   Abstract »    Full Text »
Ephrin-A5 modulates cell adhesion and morphology in an integrin-dependent manner.
A. Davy and S. M. Robbins (2000)
EMBO J. 19, 5396-5405
   Abstract »    Full Text »    PDF »
Expression of Eph receptors and ephrins is differentially regulated by E-cadherin.
S. Orsulic and R. Kemler (2000)
J. Cell Sci. 113, 1793-1802
   Abstract »    PDF »
An ephrin-A-dependent Signaling Pathway Controls Integrin Function and Is Linked to the Tyrosine Phosphorylation of a 120-kDa Protein.
J. Huai and U. Drescher (2001)
J. Biol. Chem. 276, 6689-6694
   Abstract »    Full Text »    PDF »
Activated Src Oncogene Phosphorylates R-Ras and Suppresses Integrin Activity.
J. X. Zou, Y. Liu, E. B. Pasquale, and E. Ruoslahti (2002)
J. Biol. Chem. 277, 1824-1827
   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