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

Mol. Biol. Cell 15 (5): 2176-2188

Copyright © 2004 by The American Society for Cell Biology.

Tyrosine Phosphorylation of Sprouty Proteins Regulates Their Ability to Inhibit Growth Factor Signaling: A Dual Feedback Loop

Jacqueline M. Mason *, Debra J. Morrison *, Bhramdeo Bassit *, Manjari Dimri {dagger}, Hamid Band {dagger}, Jonathan D. Licht * {ddagger}, and Isabelle Gross * {ddagger} §

* Division of Hematology/Oncology, Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029
{dagger} Evanston Northwestern Healthcare Research Institute, Evanston, Illinois 60201

Received for publication July 18, 2003. Revision received December 22, 2003. Accepted for publication January 26, 2004.

Monitoring Editor: Richard Assoian

Abstract: Sprouty proteins are recently identified receptor tyrosine kinase (RTK) inhibitors potentially involved in many developmental processes. Here, we report that Sprouty proteins become tyrosine phosphorylated after growth factor treatment. We identified Tyr55 as a key residue for Sprouty2 phosphorylation and showed that phosphorylation was required for Sprouty2 to inhibit RTK signaling, because a mutant Sprouty2 lacking Tyr55 augmented signaling. We found that tyrosine phosphorylation of Sprouty2 affected neither its subcellular localization nor its interaction with Grb2, FRS2/SNT, or other Sprouty proteins. In contrast, Sprouty2 tyrosine phosphorylation was necessary for its binding to the Src homology 2-like domain of c-Cbl after fibroblast growth factor (FGF) stimulation. To determine whether c-Cbl was required for Sprouty2-dependent cellular events, Sprouty2 was introduced into c-Cbl-wild-type and -null fibroblasts. Sprouty2 efficiently inhibited FGF-induced phosphorylation of extracellular signal-regulated kinase 1/2 in c-Cbl-null fibroblasts, thus indicating that the FGF-dependent binding of c-Cbl to Sprouty2 was dispensable for its inhibitory activity. However, c-Cbl mediates polyubiquitylation/proteasomal degradation of Sprouty2 in response to FGF. Last, using Src-family pharmacological inhibitors and dominant-negative Src, we showed that a Src-like kinase was required for tyrosine phosphorylation of Sprouty2 by growth factors. Thus, these data highlight a novel negative and positive regulatory loop that allows for the controlled, homeostatic inhibition of RTK signaling.

Article published online ahead of print. Mol. Biol. Cell 10.1091/mbc.E03–07–0503. Article and publication date are available at www.molbiolcell.org/cgi/doi/10.1091/mbc.E03–07–0503.

§ Present address: INSERM U381, 3 Avenue Molière, 67000 Strasbourg, France.

{ddagger} Corresponding authors. E-mail addresses: jonathan.licht{at}mssm.edu or isabelle.gross{at}inserm.u-strasbg.fr.

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
The Ras-GTPase activity of neurofibromin restrains ERK-dependent FGFR signaling during endochondral bone formation.
K. Ono, M. R. Karolak, J. d. l. C. Ndong, W. Wang, X. Yang, and F. Elefteriou (2013)
Hum. Mol. Genet.
   Abstract »    Full Text »    PDF »
Spry1 as a novel regulator of erythropoiesis, EPO/EPOR target, and suppressor of JAK2.
P. Sathyanarayana, A. Dev, A. Pradeep, M. Ufkin, J. D. Licht, and D. M. Wojchowski (2012)
Blood 119, 5522-5531
   Abstract »    Full Text »    PDF »
G Protein-regulated Inducer of Neurite Outgrowth (GRIN) Modulates Sprouty Protein Repression of Mitogen-activated Protein Kinase (MAPK) Activation by Growth Factor Stimulation.
T. A. Hwangpo, J. D. Jordan, P. K. Premsrirut, G. Jayamaran, J. D. Licht, R. Iyengar, and S. R. Neves (2012)
J. Biol. Chem. 287, 13674-13685
   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 »
Sprouty 2 Binds ESCRT-II Factor Eap20 and Facilitates HIV-1 Gag Release.
G. N. Medina, L. S. Ehrlich, M. H. Chen, M. B. Khan, M. D. Powell, and C. A. Carter (2011)
J. Virol. 85, 7353-7362
   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 Proteins Inhibit Receptor-mediated Activation of Phosphatidylinositol-specific Phospholipase C.
S. Akbulut, A. L. Reddi, P. Aggarwal, C. Ambardekar, B. Canciani, M. K. H. Kim, L. Hix, T. Vilimas, J. Mason, M. A. Basson, et al. (2010)
Mol. Biol. Cell 21, 3487-3496
   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 »
HECT Domain-containing E3 Ubiquitin Ligase Nedd4 Interacts with and Ubiquitinates Sprouty2.
F. Edwin, K. Anderson, and T. B. Patel (2010)
J. Biol. Chem. 285, 255-264
   Abstract »    Full Text »    PDF »
Cbl Controls EGFR Fate by Regulating Early Endosome Fusion.
G. D. Visser Smit, T. L. Place, S. L. Cole, K. A. Clausen, S. Vemuganti, G. Zhang, J. G. Koland, and N. L. Lill (2009)
Science Signaling 2, ra86
   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 »
Cell Density-Dependent Inhibition of Epidermal Growth Factor Receptor Signaling by p38{alpha} Mitogen-Activated Protein Kinase via Sprouty2 Downregulation.
A. Swat, I. Dolado, J. M. Rojas, and A. R. Nebreda (2009)
Mol. Cell. Biol. 29, 3332-3343
   Abstract »    Full Text »    PDF »
Sprouty2-Mediated Inhibition of Fibroblast Growth Factor Signaling Is Modulated by the Protein Kinase DYRK1A.
S. Aranda, M. Alvarez, S. Turro, A. Laguna, and S. de la Luna (2008)
Mol. Cell. Biol. 28, 5899-5911
   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 »
Evidence That Sprouty 2 Is Necessary for Sarcoma Formation by H-Ras Oncogene-transformed Human Fibroblasts.
P. Lito, B. D. Mets, S. Kleff, S. O'Reilly, V. M. Maher, and J. J. McCormick (2008)
J. Biol. Chem. 283, 2002-2009
   Abstract »    Full Text »    PDF »
Tesk1 Interacts with Spry2 to Abrogate Its Inhibition of ERK Phosphorylation Downstream of Receptor Tyrosine Kinase Signaling.
S. Chandramouli, C. Y. Yu, P. Yusoff, D.-H. Lao, H. F. Leong, K. Mizuno, and G. R. Guy (2008)
J. Biol. Chem. 283, 1679-1691
   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 »
Direct Binding of PP2A to Sprouty2 and Phosphorylation Changes Are a Prerequisite for ERK Inhibition Downstream of Fibroblast Growth Factor Receptor Stimulation.
D.-H. Lao, P. Yusoff, S. Chandramouli, R. J. Philp, C. W. Fong, R. A. Jackson, T. Y. Saw, C. Y. Yu, and G. R. Guy (2007)
J. Biol. Chem. 282, 9117-9126
   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 Src Homology 3-binding Sequence on the C Terminus of Sprouty2 Is Necessary for Inhibition of the Ras/ERK Pathway Downstream of Fibroblast Growth Factor Receptor Stimulation.
D.-H. Lao, S. Chandramouli, P. Yusoff, C. W. Fong, T. Y. Saw, L. P. Tai, C. Y. Yu, H. F. Leong, and G. R. Guy (2006)
J. Biol. Chem. 281, 29993-30000
   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 »
Sprouty2 Is Involved in Male Sex Organogenesis by Controlling Fibroblast Growth Factor 9-Induced Mesonephric Cell Migration to the Developing Testis.
L. Chi, P. Itaranta, S. Zhang, and S. Vainio (2006)
Endocrinology 147, 3777-3788
   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 »
Regulation of Sprouty Stability by Mnk1-Dependent Phosphorylation.
J. DaSilva, L. Xu, H. J. Kim, W. T. Miller, and D. Bar-Sagi (2006)
Mol. Cell. Biol. 26, 1898-1907
   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 »
Phosphorylation of Carboxyl-terminal Tyrosines Modulates the Specificity of Sprouty-2 Inhibition of Different Signaling Pathways.
C. Rubin, Y. Zwang, N. Vaisman, D. Ron, and Y. Yarden (2005)
J. Biol. Chem. 280, 9735-9744
   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 »
Regulatory Mechanisms and Function of ERK MAP Kinases.
S. Torii, K. Nakayama, T. Yamamoto, and E. Nishida (2004)
J. Biochem. 136, 557-561
   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 »

To Advertise     Find Products

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