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

J. Biol. Chem. 276 (6): 4128-4133

© 2001 by The American Society for Biochemistry and Molecular Biology, Inc.

Inhibition of Angiogenesis by a Mouse Sprouty Protein*

Sang Hoon LeeDagger , Derrick J. SchlossDagger , Lesley Jarvis§, Mark A. Krasnow§, and Judith L. SwainDagger

From the Dagger  Department of Medicine, § Howard Hughes Medical Institute, Department of Biochemistry, Stanford University School of Medicine, S-102, Stanford, California 94305-5109

Sprouty negatively modulates branching morphogenesis in the Drosophila tracheal system. To address the role of mammalian Sprouty homologues in angiogenesis, another form of branching morphogenesis, a recombinant adenovirus engineered to express murine Sprouty-4 selectively in endothelial cells, was injected into the sinus venosus of embryonic day 9.0 cultured mouse embryos. Sprouty-4 expression inhibited branching and sprouting of small vessels, resulting in abnormal embryonic development. In vitro, Sprouty-4 inhibited fibroblast growth factor and vascular endothelial cell growth factor-mediated cell proliferation and migration and prevented basic fibroblast growth factor and vascular endothelial cell growth factor-induced MAPK phosphorylation in endothelial cells, indicating inhibition of tyrosine kinase-mediated signaling pathways. The ability of constitutively activated mutant RasL61 to rescue Sprouty-4 inhibition of MAPK phosphorylation suggests that Sprouty inhibits receptor tyrosine kinase signaling upstream of Ras. Thus, Sprouty may regulate angiogenesis in normal and disease processes by modulating signaling by endothelial tyrosine kinases.

* This work was supported by National Institutes of Health (NIH) Grants HL 26831 (to J. L. S.) and T32 HL07708 (to S. H. L.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Department of Medicine, Stanford University, S-102, 300 Pasteur Dr., Stanford, CA 94305-5109. Tel.: 650-489-7778; Fax: 650-725-8381; E-mail:

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.

c-MYC-regulated miR-23a/24-2/27a Cluster Promotes Mammary Carcinoma Cell Invasion and Hepatic Metastasis by Targeting Sprouty2.
X. Li, X. Liu, W. Xu, P. Zhou, P. Gao, S. Jiang, P. E. Lobie, and T. Zhu (2013)
J. Biol. Chem. 288, 18121-18133
   Abstract »    Full Text »    PDF »
MicroRNA-10 Regulates the Angiogenic Behavior of Zebrafish and Human Endothelial Cells by Promoting Vascular Endothelial Growth Factor Signaling.
D. Hassel, P. Cheng, M. P. White, K. N. Ivey, J. Kroll, H. G. Augustin, H. A. Katus, D. Y. R. Stainier, and D. Srivastava (2012)
Circ. Res. 111, 1421-1433
   Abstract »    Full Text »    PDF »
Regulation of Cellular Levels of Sprouty2 Protein by Prolyl Hydroxylase Domain and von Hippel-Lindau Proteins.
K. Anderson, K. A. Nordquist, X. Gao, K. C. Hicks, B. Zhai, S. P. Gygi, and T. B. Patel (2011)
J. Biol. Chem. 286, 42027-42036
   Abstract »    Full Text »    PDF »
Sprouty2 downregulates angiogenesis during mouse skin wound healing.
M. S. Wietecha, L. Chen, M. J. Ranzer, K. Anderson, C. Ying, T. B. Patel, and L. A. DiPietro (2011)
Am J Physiol Heart Circ Physiol 300, H459-H467
   Abstract »    Full Text »    PDF »
Sprouty-4 Inhibits Transformed Cell Growth, Migration and Invasion, and Epithelial-Mesenchymal Transition, and Is Regulated by Wnt7A through PPAR{gamma} in Non-Small Cell Lung Cancer.
M. A. Tennis, M. M. Van Scoyk, S. V. Freeman, K. M. Vandervest, R. A. Nemenoff, and R. A. Winn (2010)
Mol. Cancer Res. 8, 833-843
   Abstract »    Full Text »    PDF »
Intermolecular Interactions of Sprouty Proteins and Their Implications in Development and Disease.
F. Edwin, K. Anderson, C. Ying, and T. B. Patel (2009)
Mol. Pharmacol. 76, 679-691
   Abstract »    Full Text »    PDF »
Dioxin Receptor Deficiency Impairs Angiogenesis by a Mechanism Involving VEGF-A Depletion in the Endothelium and Transforming Growth Factor-{beta} Overexpression in the Stroma.
A. C. Roman, J. M. Carvajal-Gonzalez, E. M. Rico-Leo, and P. M. Fernandez-Salguero (2009)
J. Biol. Chem. 284, 25135-25148
   Abstract »    Full Text »    PDF »
MicroRNA-21 Targets Sprouty2 and Promotes Cellular Outgrowths.
D. Sayed, S. Rane, J. Lypowy, M. He, I.-Y. Chen, H. Vashistha, L. Yan, A. Malhotra, D. Vatner, and M. Abdellatif (2008)
Mol. Biol. Cell 19, 3272-3282
   Abstract »    Full Text »    PDF »
Modulation of Endocrine Pancreas Development but not {beta}-Cell Carcinogenesis by Sprouty4.
F. Jaggi, M. A. Cabrita, A.-K. T. Perl, and G. Christofori (2008)
Mol. Cancer Res. 6, 468-482
   Abstract »    Full Text »    PDF »
A Novel Role of Sprouty 2 in Regulating Cellular Apoptosis.
F. Edwin and T. B. Patel (2008)
J. Biol. Chem. 283, 3181-3190
   Abstract »    Full Text »    PDF »
Spreds Are Essential for Embryonic Lymphangiogenesis by Regulating Vascular Endothelial Growth Factor Receptor 3 Signaling.
K. Taniguchi, R.-i. Kohno, T. Ayada, R. Kato, K. Ichiyama, T. Morisada, Y. Oike, Y. Yonemitsu, Y. Maehara, and A. Yoshimura (2007)
Mol. Cell. Biol. 27, 4541-4550
   Abstract »    Full Text »    PDF »
Down-Regulation of Sprouty2 in Non-Small Cell Lung Cancer Contributes to Tumor Malignancy via Extracellular Signal-Regulated Kinase Pathway-Dependent and -Independent Mechanisms.
H. Sutterluty, C.-E. Mayer, U. Setinek, J. Attems, S. Ovtcharov, M. Mikula, W. Mikulits, M. Micksche, and W. Berger (2007)
Mol. Cancer Res. 5, 509-520
   Abstract »    Full Text »    PDF »
The VASP-Spred-Sprouty Domain Puzzle.
K. Bundschu, U. Walter, and K. Schuh (2006)
J. Biol. Chem. 281, 36477-36481
   Abstract »    Full Text »    PDF »
A Functional Interaction between Sprouty Proteins and Caveolin-1.
M. A. Cabrita, F. Jaggi, S. P. Widjaja, and G. Christofori (2006)
J. Biol. Chem. 281, 29201-2912
   Abstract »    Full Text »    PDF »
Dual Effects of Sprouty1 on TCR Signaling Depending on the Differentiation State of the T Cell.
H. Choi, S.-Y. Cho, R. H. Schwartz, and K. Choi (2006)
J. Immunol. 176, 6034-6045
   Abstract »    Full Text »    PDF »
Sprouty proteins are in vivo targets of Corkscrew/SHP-2 tyrosine phosphatases.
L. A. Jarvis, S. J. Toering, M. A. Simon, M. A. Krasnow, and R. K. Smith-Bolton (2006)
Development 133, 1133-1142
   Abstract »    Full Text »    PDF »
The Tumor Suppressor PTEN Is Necessary for Human Sprouty 2-mediated Inhibition of Cell Proliferation.
F. Edwin, R. Singh, R. Endersby, S. J. Baker, and T. B. Patel (2006)
J. Biol. Chem. 281, 4816-4822
   Abstract »    Full Text »    PDF »
Sprouty 2, an Inhibitor of Mitogen-Activated Protein Kinase Signaling, Is Down-Regulated in Hepatocellular Carcinoma.
C. W. Fong, M.-S. Chua, A. B. McKie, S. H. M. Ling, V. Mason, R. Li, P. Yusoff, T. L. Lo, H. Y. Leung, S. K.S. So, et al. (2006)
Cancer Res. 66, 2048-2058
   Abstract »    Full Text »    PDF »
Efficient suppression of FGF-2-induced ERK activation by the cooperative interaction among mammalian Sprouty isoforms.
K.-i. Ozaki, S. Miyazaki, S. Tanimura, and M. Kohno (2005)
J. Cell Sci. 118, 5861-5871
   Abstract »    Full Text »    PDF »
Sprouty-2 Overexpression in C2C12 Cells Confers Myogenic Differentiation Properties in the Presence of FGF2.
C. de Alvaro, N. Martinez, J. M. Rojas, and M. Lorenzo (2005)
Mol. Biol. Cell 16, 4454-4461
   Abstract »    Full Text »    PDF »
Gene Disruption of Spred-2 Causes Dwarfism.
K. Bundschu, K.-P. Knobeloch, M. Ullrich, T. Schinke, M. Amling, C. M. Engelhardt, T. Renne, U. Walter, and K. Schuh (2005)
J. Biol. Chem. 280, 28572-28580
   Abstract »    Full Text »    PDF »
Expression and regulation of Sprouty-2 in the granulosa-lutein cells of the corpus luteum.
R. Haimov-Kochman, A. Ravhon, D. Prus, C. Greenfield, Z. Finci-Yeheskel, D. S.Goldman-Wohl, S. Natanson-Yaron, R. Reich, S. Yagel, and A. Hurwitz (2005)
Mol. Hum. Reprod. 11, 537-542
   Abstract »    Full Text »    PDF »
Regulation of Vascular Smooth Muscle Cell Proliferation and Migration by Human Sprouty 2.
C. Zhang, D. Chaturvedi, L. Jaggar, D. Magnuson, J. M. Lee, and T. B. Patel (2005)
Arterioscler Thromb Vasc Biol 25, 533-538
   Abstract »    Full Text »    PDF »
Spred-1 Negatively Regulates Interleukin-3-mediated ERK/Mitogen-activated Protein (MAP) Kinase Activation in Hematopoietic Cells.
A. Nonami, R. Kato, K. Taniguchi, D. Yoshiga, T. Taketomi, S. Fukuyama, M. Harada, A. Sasaki, and A. Yoshimura (2004)
J. Biol. Chem. 279, 52543-52551
   Abstract »    Full Text »    PDF »
FRS2-dependent SRC activation is required for fibroblast growth factor receptor-induced phosphorylation of Sprouty and suppression of ERK activity.
X. Li, V. G. Brunton, H. R. Burgar, L. M. Wheldon, and J. K. Heath (2004)
J. Cell Sci. 117, 6007-6017
   Abstract »    Full Text »    PDF »
The Ras/Mitogen-Activated Protein Kinase Pathway Inhibitor and Likely Tumor Suppressor Proteins, Sprouty 1 and Sprouty 2 Are Deregulated in Breast Cancer.
T. L. Lo, P. Yusoff, C. W. Fong, K. Guo, B. J. McCaw, W. A. Phillips, H. Yang, E. S. M. Wong, H. F. Leong, Q. Zeng, et al. (2004)
Cancer Res. 64, 6127-6136
   Abstract »    Full Text »    PDF »
Identification and regulation of Sprouty1, a negative inhibitor of the ERK cascade, in the human heart.
R. C. Huebert, Q. Li, N. Adhikari, N. J. Charles, X. Han, M.-K. Ezzat, S. Grindle, S. Park, S. Ormaza, D. Fermin, et al. (2004)
Physiol Genomics 18, 284-289
   Abstract »    Full Text »    PDF »
The Expression of Sprouty1, an Inhibitor of Fibroblast Growth Factor Signal Transduction, Is Decreased in Human Prostate Cancer.
B. Kwabi-Addo, J. Wang, H. Erdem, A. Vaid, P. Castro, G. Ayala, and M. Ittmann (2004)
Cancer Res. 64, 4728-4735
   Abstract »    Full Text »    PDF »
Genomic structure and promoter characterization of the human Sprouty4 gene, a novel regulator of lung morphogenesis.
W. Ding, S. Bellusci, W. Shi, and D. Warburton (2004)
Am J Physiol Lung Cell Mol Physiol 287, L52-L59
   Abstract »    Full Text »    PDF »
Tyrosine Phosphorylation of Sprouty Proteins Regulates Their Ability to Inhibit Growth Factor Signaling: A Dual Feedback Loop.
J. M. Mason, D. J. Morrison, B. Bassit, M. Dimri, H. Band, J. D. Licht, and I. Gross (2004)
Mol. Biol. Cell 15, 2176-2188
   Abstract »    Full Text »    PDF »
Tyrosine Phosphorylation of Sprouty2 Enhances Its Interaction with c-Cbl and Is Crucial for Its Function.
C. W. Fong, H. F. Leong, E. S. M. Wong, J. Lim, P. Yusoff, and G. R. Guy (2003)
J. Biol. Chem. 278, 33456-33464
   Abstract »    Full Text »    PDF »
Sprouty: how does the branch manager work?.
G. R. Guy, E. S. M. Wong, P. Yusoff, S. Chandramouli, T. L. Lo, J. Lim, and C. W. Fong (2003)
J. Cell Sci. 116, 3061-3068
   Abstract »    Full Text »    PDF »
Protein-tyrosine Phosphatase-1B (PTP1B) Mediates the Anti-migratory Actions of Sprouty.
Y. Yigzaw, H. M. Poppleton, N. Sreejayan, A. Hassid, and T. B. Patel (2003)
J. Biol. Chem. 278, 284-288
   Abstract »    Full Text »    PDF »
Spatially restricted patterning cues provided by heparin-binding VEGF-A control blood vessel branching morphogenesis.
C. Ruhrberg, H. Gerhardt, M. Golding, R. Watson, S. Ioannidou, H. Fujisawa, C. Betsholtz, and D. T. Shima (2002)
Genes & Dev. 16, 2684-2698
   Abstract »    Full Text »    PDF »
Sprouty2 attenuates epidermal growth factor receptor ubiquitylation and endocytosis, and consequently enhances Ras/ERK signalling.
E. S. M. Wong, C. W. Fong, J. Lim, P. Yusoff, B. C. Low, W. Y. Langdon, and G. R. Guy (2002)
EMBO J. 21, 4796-4808
   Abstract »    Full Text »    PDF »
The bimodal regulation of epidermal growth factor signaling by human Sprouty proteins.
J. E. Egan, A. B. Hall, B. A. Yatsula, and D. Bar-Sagi (2002)
PNAS 99, 6041-6046
   Abstract »    Full Text »    PDF »
Sprouty2 Inhibits the Ras/MAP Kinase Pathway by Inhibiting the Activation of Raf.
P. Yusoff, D.-H. Lao, S. H. Ong, E. S. M. Wong, J. Lim, T. L. Lo, H. F. Leong, C. W. Fong, and G. R. Guy (2002)
J. Biol. Chem. 277, 3195-3201
   Abstract »    Full Text »    PDF »
Differential gene expression during capillary morphogenesis in 3D collagen matrices: regulated expression of genes involved in basement membrane matrix assembly, cell cycle progression, cellular differentiation and G-protein signaling.
S. E. Bell, A. Mavila, R. Salazar, K. J. Bayless, S. Kanagala, S. A. Maxwell, and G. E. Davis (2001)
J. Cell Sci. 114, 2755-2773
   Abstract »    Full Text »    PDF »
Identification of a Dominant Negative Mutant of Sprouty That Potentiates Fibroblast Growth Factor- but Not Epidermal Growth Factor-induced ERK Activation.
A. Sasaki, T. Taketomi, T. Wakioka, R. Kato, and A. Yoshimura (2001)
J. Biol. Chem. 276, 36804-36808
   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