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

Science 301 (5629): 94-96

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

Role of Raf in Vascular Protection from Distinct Apoptotic Stimuli

Alireza Alavi,* John D. Hood,* Ricardo Frausto, Dwayne G. Stupack, David A. Cheresh{dagger}

Abstract: Raf kinases have been linked to endothelial cell survival. Here, we show that basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) differentially activate Raf, resulting in protection from distinct pathways of apoptosis in human endothelial cells and chick embryo vasculature. bFGF activated Raf-1 via p21-activated protein kinase–1 (PAK-1) phosphorylation of serines 338 and 339, resulting in Raf-1 mitochondrial translocation and endothelial cell protection from the intrinsic pathway of apoptosis, independent of the mitogen-activated protein kinase kinase–1 (MEK1). In contrast, VEGF activated Raf-1 via Src kinase, leading to phosphorylation of tyrosines 340 and 341 and MEK1-dependent protection from extrinsic-mediated apoptosis. These findings implicate Raf-1 as a pivotal regulator of endothelial cell survival during angiogenesis.

Department of Immunology, Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.

Back to Top

* These authors contributed equally to this work.

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

Unique Cerebrovascular Anomalies in Noonan Syndrome With RAF1 Mutation.
Y. A. Zarate, A. W. Lichty, K. J. Champion, L. K. Clarkson, K. R. Holden, and M. G. Matheus (2013)
J Child Neurol
   Abstract »    Full Text »    PDF »
Essential Role for Endocytosis in the Growth Factor-stimulated Activation of ERK1/2 in Endothelial Cells.
M. Gourlaouen, J. C. Welti, N. S. Vasudev, and A. R. Reynolds (2013)
J. Biol. Chem. 288, 7467-7480
   Abstract »    Full Text »    PDF »
The Role of the 3D Environment in Hypoxia-induced Drug and Apoptosis Resistance.
J. W. KIM, W. J. HO, and B. M. WU (2011)
Anticancer Res 31, 3237-3245
   Abstract »    Full Text »    PDF »
{alpha}v Integrins in Angiogenesis and Cancer.
S. M. Weis and D. A. Cheresh (2011)
Cold Spring Harb Perspect Med 1, a006478
   Abstract »    Full Text »    PDF »
Targets of Raf in tumorigenesis.
T. S. Niault and M. Baccarini (2010)
Carcinogenesis 31, 1165-1174
   Abstract »    Full Text »    PDF »
Endothelial lumen signaling complexes control 3D matrix-specific tubulogenesis through interdependent Cdc42- and MT1-MMP-mediated events.
A. Sacharidou, W. Koh, A. N. Stratman, A. M. Mayo, K. E. Fisher, and G. E. Davis (2010)
Blood 115, 5259-5269
   Abstract »    Full Text »    PDF »
Disruption of angiogenesis and tumor growth with an orally active drug that stabilizes the inactive state of PDGFR{beta}/B-RAF.
E. A. Murphy, D. J. Shields, K. Stoletov, E. Dneprovskaia, M. McElroy, J. I. Greenberg, J. Lindquist, L. M. Acevedo, S. Anand, B. K. Majeti, et al. (2010)
PNAS 107, 4299-4304
   Abstract »    Full Text »    PDF »
AZD6244 (ARRY-142886) enhances the therapeutic efficacy of sorafenib in mouse models of gastric cancer.
S. Yang, V. C. Ngo, G. B. Lew, L. W. V. Chong, S. S. Lee, W. J. R. Ong, W. L. I. Lam, C. H. Thng, H. N. Koong, H. S. Ong, et al. (2009)
Mol. Cancer Ther. 8, 2537-2545
   Abstract »    Full Text »    PDF »
Ets1 and Ets2 are required for endothelial cell survival during embryonic angiogenesis.
G. Wei, R. Srinivasan, C. Z. Cantemir-Stone, S. M. Sharma, R. Santhanam, M. Weinstein, N. Muthusamy, A. K. Man, R. G. Oshima, G. Leone, et al. (2009)
Blood 114, 1123-1130
   Abstract »    Full Text »    PDF »
Formation of endothelial lumens requires a coordinated PKC{epsilon}-, Src-, Pak- and Raf-kinase-dependent signaling cascade downstream of Cdc42 activation.
W. Koh, K. Sachidanandam, A. N. Stratman, A. Sacharidou, A. M. Mayo, E. A. Murphy, D. A. Cheresh, and G. E. Davis (2009)
J. Cell Sci. 122, 1812-1822
   Abstract »    Full Text »    PDF »
A. Fischer, A. Baljuls, J. Reinders, E. Nekhoroshkova, C. Sibilski, R. Metz, S. Albert, K. Rajalingam, M. Hekman, and U. R. Rapp (2009)
J. Biol. Chem. 284, 3183-3194
   Abstract »    Full Text »    PDF »
Disruption of the Transcription Factor Nrf2 Promotes Pro-Oxidative Dendritic Cells That Stimulate Th2-Like Immunoresponsiveness upon Activation by Ambient Particulate Matter.
M. A. Williams, T. Rangasamy, S. M. Bauer, S. Killedar, M. Karp, T. W. Kensler, M. Yamamoto, P. Breysse, S. Biswal, and S. N. Georas (2008)
J. Immunol. 181, 4545-4559
   Abstract »    Full Text »    PDF »
Selected Combination Therapy with Sorafenib: A Review of Clinical Data and Perspectives in Advanced Solid Tumors.
L. Dal Lago, V. D'Hondt, and A. Awada (2008)
Oncologist 13, 845-858
   Abstract »    Full Text »    PDF »
Isoform-specific Interaction of C-RAF with Mitochondria.
A. Galmiche, J. Fueller, A. Santel, G. Krohne, I. Wittig, A. Doye, M. Rolando, G. Flatau, E. Lemichez, and U. R. Rapp (2008)
J. Biol. Chem. 283, 14857-14866
   Abstract »    Full Text »    PDF »
A Small Molecule Disruptor of Rb/Raf-1 Interaction Inhibits Cell Proliferation, Angiogenesis, and Growth of Human Tumor Xenografts in Nude Mice.
R. Kinkade, P. Dasgupta, A. Carie, D. Pernazza, M. Carless, S. Pillai, N. Lawrence, S. M. Sebti, and S. Chellappan (2008)
Cancer Res. 68, 3810-3818
   Abstract »    Full Text »    PDF »
Distinct Angiogenic Mediators Are Required for Basic Fibroblast Growth Factor- and Vascular Endothelial Growth Factor-induced Angiogenesis: The Role of Cytoplasmic Tyrosine Kinase c-Abl in Tumor Angiogenesis.
W. Yan, B. Bentley, and R. Shao (2008)
Mol. Biol. Cell 19, 2278-2288
   Abstract »    Full Text »    PDF »
Homocysteine Inhibits Arterial Endothelial Cell Growth Through Transcriptional Downregulation of Fibroblast Growth Factor-2 Involving G Protein and DNA Methylation.
P.-Y. Chang, S.-C. Lu, C.-M. Lee, Y.-J. Chen, T. A. Dugan, W.-H. Huang, S.-F. Chang, W. S.L. Liao, C.-H. Chen, and Y.-T. Lee (2008)
Circ. Res. 102, 933-941
   Abstract »    Full Text »    PDF »
KLF2 Transcription Factor Modulates Blood Vessel Maturation through Smooth Muscle Cell Migration.
J. Wu, C. S. Bohanan, J. C. Neumann, and J. B. Lingrel (2008)
J. Biol. Chem. 283, 3942-3950
   Abstract »    Full Text »    PDF »
Combining Agents that Target the Tumor Microenvironment Improves the Efficacy of Anticancer Therapy.
J. A. Blansfield, D. Caragacianu, H. R. Alexander III, M. A. Tangrea, S. Y. Morita, D. Lorang, P. Schafer, G. Muller, D. Stirling, R. E. Royal, et al. (2008)
Clin. Cancer Res. 14, 270-280
   Abstract »    Full Text »    PDF »
Review: Side Effects of Approved Molecular Targeted Therapies in Solid Cancers.
C. Widakowich, G. de Castro Jr., E. de Azambuja, P. Dinh, and A. Awada (2007)
Oncologist 12, 1443-1455
   Abstract »    Full Text »    PDF »
NADPH Oxidase Activity Selectively Modulates Vascular Endothelial Growth Factor Signaling Pathways.
Md. R. Abid, K. C. Spokes, S.-C. Shih, and W. C. Aird (2007)
J. Biol. Chem. 282, 35373-35385
   Abstract »    Full Text »    PDF »
JAK2 Tyrosine Kinase Phosphorylates PAK1 and Regulates PAK1 Activity and Functions.
L. Rider, A. Shatrova, E. P. Feener, L. Webb, and M. Diakonova (2007)
J. Biol. Chem. 282, 30985-30996
   Abstract »    Full Text »    PDF »
Src Family Kinases Promote Vessel Stability by Antagonizing the Rho/ROCK Pathway.
E. Im and A. Kazlauskas (2007)
J. Biol. Chem. 282, 29122-29129
   Abstract »    Full Text »    PDF »
Grb10 and Active Raf-1 Kinase Promote Bad-dependent Cell Survival.
S. Kebache, J. Ash, M. G. Annis, J. Hagan, M. Huber, J. Hassard, C. L. Stewart, M. Whiteway, and A. Nantel (2007)
J. Biol. Chem. 282, 21873-21883
   Abstract »    Full Text »    PDF »
Chemoresistance of Endothelial Cells Induced by Basic Fibroblast Growth Factor Depends on Raf-1-Mediated Inhibition of the Proapoptotic Kinase, ASK1.
A. S. Alavi, L. Acevedo, W. Min, and D. A. Cheresh (2007)
Cancer Res. 67, 2766-2772
   Abstract »    Full Text »    PDF »
The power and promise of "rewiring" the mitogen-activated protein kinase network in prostate cancer therapeutics.
A. G. Papatsoris, M. V. Karamouzis, and A. G. Papavassiliou (2007)
Mol. Cancer Ther. 6, 811-819
   Abstract »    Full Text »    PDF »
Controlled Release of Basic Fibroblast Growth Factor From Gelatin Hydrogel Sheet Improves Structural and Physiological Properties of Vein Graft in Rat.
T. Haraguchi, K. Okada, Y. Tabata, Y. Maniwa, Y. Hayashi, and Y. Okita (2007)
Arterioscler Thromb Vasc Biol 27, 548-555
   Abstract »    Full Text »    PDF »
Sorafenib and Sunitinib in the Treatment of Advanced Non-Small Cell Lung Cancer.
C. Gridelli, P. Maione, F. Del Gaizo, G. Colantuoni, C. Guerriero, C. Ferrara, D. Nicolella, D. Comunale, A. De Vita, and A. Rossi (2007)
Oncologist 12, 191-200
   Abstract »    Full Text »    PDF »
Cortical Migration Defects in Mice Expressing A-RAF from the B-RAF Locus.
G. Camarero, O. Y. Tyrsin, C. Xiang, V. Pfeiffer, S. Pleiser, S. Wiese, R. Gotz, and U. R. Rapp (2006)
Mol. Cell. Biol. 26, 7103-7115
   Abstract »    Full Text »    PDF »
Protective effects of epoxyeicosatrienoic acids on human endothelial cells from the pulmonary and coronary vasculature.
A. Dhanasekaran, R. Al-Saghir, B. Lopez, D. Zhu, D. D. Gutterman, E. R. Jacobs, and M. Medhora (2006)
Am J Physiol Heart Circ Physiol 291, H517-H531
   Abstract »    Full Text »    PDF »
Focal Adhesion Kinase Controls Cellular Levels of p27/Kip1 and p21/Cip1 through Skp2-Dependent and -Independent Mechanisms.
P. Bryant, Q. Zheng, and K. Pumiglia (2006)
Mol. Cell. Biol. 26, 4201-4213
   Abstract »    Full Text »    PDF »
Results of a Phase I trial of sorafenib (BAY 43-9006) in combination with doxorubicin in patients with refractory solid tumors.
H. Richly, B. F. Henning, P. Kupsch, K. Passarge, M. Grubert, R. A. Hilger, O. Christensen, E. Brendel, B. Schwartz, M. Ludwig, et al. (2006)
Ann. Onc. 17, 866-873
   Abstract »    Full Text »    PDF »
Mechanisms of Hypertension Associated With BAY 43-9006.
M. L. Veronese, A. Mosenkis, K. T. Flaherty, M. Gallagher, J. P. Stevenson, R. R. Townsend, and P. J. O'Dwyer (2006)
J. Clin. Oncol. 24, 1363-1369
   Abstract »    Full Text »    PDF »
Endothelial FAK is essential for vascular network stability, cell survival, and lamellipodial formation.
R. Braren, H. Hu, Y. H. Kim, H. E. Beggs, L. F. Reichardt, and R. Wang (2006)
J. Cell Biol. 172, 151-162
   Abstract »    Full Text »    PDF »
Role of Group A p21-activated Kinases in Activation of Extracellular-regulated Kinase by Growth Factors.
A. Beeser, Z. M. Jaffer, C. Hofmann, and J. Chernoff (2005)
J. Biol. Chem. 280, 36609-36615
   Abstract »    Full Text »    PDF »
Raf: A Strategic Target for Therapeutic Development Against Cancer.
M. Beeram, A. Patnaik, and E. K. Rowinsky (2005)
J. Clin. Oncol. 23, 6771-6790
   Abstract »    Full Text »    PDF »
Endothelial intercellular adhesion molecule (ICAM)-2 regulates angiogenesis.
M.-T. Huang, J. C. Mason, G. M. Birdsey, V. Amsellem, N. Gerwin, D. O. Haskard, A. J. Ridley, and A. M. Randi (2005)
Blood 106, 1636-1643
   Abstract »    Full Text »    PDF »
p21-activated Kinase 1 (Pak1)-dependent Phosphorylation of Raf-1 Regulates Its Mitochondrial Localization, Phosphorylation of BAD, and Bcl-2 Association.
S. Jin, Y. Zhuo, W. Guo, and J. Field (2005)
J. Biol. Chem. 280, 24698-24705
   Abstract »    Full Text »    PDF »
CNK1 Is a Scaffold Protein That Regulates Src-mediated Raf-1 Activation.
A. Ziogas, K. Moelling, and G. Radziwill (2005)
J. Biol. Chem. 280, 24205-24211
   Abstract »    Full Text »    PDF »
Disruption of the Shc/Grb2 Complex during Abelson Virus Transformation Affects Proliferation, but Not Apoptosis.
L. B. Baughn and N. Rosenberg (2005)
J. Virol. 79, 2325-2334
   Abstract »    Full Text »    PDF »
Vascular endothelial growth factor and related molecules in acute lung injury.
M. Mura, C. C. dos Santos, D. Stewart, and M. Liu (2004)
J Appl Physiol 97, 1605-1617
   Abstract »    Full Text »    PDF »
Disruption of the Rb-Raf-1 Interaction Inhibits Tumor Growth and Angiogenesis.
P. Dasgupta, J. Sun, S. Wang, G. Fusaro, V. Betts, J. Padmanabhan, S. M. Sebti, and S. P. Chellappan (2004)
Mol. Cell. Biol. 24, 9527-9541
   Abstract »    Full Text »    PDF »
Vascular Endothelial Growth Factor-mediated Induction of Manganese Superoxide Dismutase Occurs through Redox-dependent Regulation of Forkhead and I{kappa}B/NF-{kappa}B.
Md. R. Abid, I. G. Schoots, K. C. Spokes, S.-Q. Wu, C. Mawhinney, and W. C. Aird (2004)
J. Biol. Chem. 279, 44030-44038
   Abstract »    Full Text »    PDF »
BAY 43-9006 Exhibits Broad Spectrum Oral Antitumor Activity and Targets the RAF/MEK/ERK Pathway and Receptor Tyrosine Kinases Involved in Tumor Progression and Angiogenesis.
S. M. Wilhelm, C. Carter, L. Tang, D. Wilkie, A. McNabola, H. Rong, C. Chen, X. Zhang, P. Vincent, M. McHugh, et al. (2004)
Cancer Res. 64, 7099-7109
   Abstract »    Full Text »    PDF »
Array Comparative Genomic Hybridization Analysis of Colorectal Cancer Cell Lines and Primary Carcinomas.
E. J. Douglas, H. Fiegler, A. Rowan, S. Halford, D. C. Bicknell, W. Bodmer, I. P. M. Tomlinson, and N. P. Carter (2004)
Cancer Res. 64, 4817-4825
   Abstract »    Full Text »    PDF »
Nuclear Export of Phosphorylated Galectin-3 Regulates Its Antiapoptotic Activity in Response to Chemotherapeutic Drugs.
Y. Takenaka, T. Fukumori, T. Yoshii, N. Oka, H. Inohara, H.-R. C. Kim, R. S. Bresalier, and A. Raz (2004)
Mol. Cell. Biol. 24, 4395-4406
   Abstract »    Full Text »    PDF »
Dynamic Changes in C-Raf Phosphorylation and 14-3-3 Protein Binding in Response to Growth Factor Stimulation: DIFFERENTIAL ROLES OF 14-3-3 PROTEIN BINDING SITES.
M. Hekman, S. Wiese, R. Metz, S. Albert, J. Troppmair, J. Nickel, M. Sendtner, and U. R. Rapp (2004)
J. Biol. Chem. 279, 14074-14086
   Abstract »    Full Text »    PDF »
Adenovirus E4 Gene Promotes Selective Endothelial Cell Survival and Angiogenesis via Activation of the Vascular Endothelial-Cadherin/Akt Signaling Pathway.
F. Zhang, J. Cheng, N. R. Hackett, G. Lam, K. Shido, R. Pergolizzi, D. K. Jin, R. G. Crystal, and S. Rafii (2004)
J. Biol. Chem. 279, 11760-11766
   Abstract »    Full Text »    PDF »
P21Waf1/Cip1 in endothelial cell survival.
F. Aoudjit and J. Sevigny (2004)
Cardiovasc Res 61, 648-650
   Full Text »    PDF »
SU1498, an Inhibitor of Vascular Endothelial Growth Factor Receptor 2, Causes Accumulation of Phosphorylated ERK Kinases and Inhibits Their Activity in Vivo and in Vitro.
G. Boguslawski, P. W. McGlynn, K. A. Harvey, and A. T. Kovala (2004)
J. Biol. Chem. 279, 5716-5724
   Abstract »    Full Text »    PDF »
Etk/Bmx Transactivates Vascular Endothelial Growth Factor 2 and Recruits Phosphatidylinositol 3-Kinase to Mediate the Tumor Necrosis Factor-induced Angiogenic Pathway.
R. Zhang, Y. Xu, N. Ekman, Z. Wu, J. Wu, K. Alitalo, and W. Min (2003)
J. Biol. Chem. 278, 51267-51276
   Abstract »    Full Text »    PDF »
Differential {alpha}v integrin-mediated Ras-ERK signaling during two pathways of angiogenesis.
J. D. Hood, R. Frausto, W. B. Kiosses, M. A. Schwartz, and D. A. Cheresh (2003)
J. Cell Biol. 162, 933-943
   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