Sprouty proteins: antagonists of endothelial cell signaling and more

Miguel A. Cabrita; Gerhard Christofori

doi:10.1160/TH03-04-0217

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2003; 90(04): 586-590
DOI: 10.1160/TH03-04-0217

Review Article

Schattauer GmbH

Sprouty proteins: antagonists of endothelial cell signaling and more

Miguel A. Cabrita

¹Institute of Biochemistry and Genetics, Department of Clinical-Biological Sciences, University of Basel, Switzerland

,

Gerhard Christofori

¹Institute of Biochemistry and Genetics, Department of Clinical-Biological Sciences, University of Basel, Switzerland

› Author Affiliations

Abstract

Summary

Among many signaling pathways, receptor tyrosine kinases (RTKs) can activate the mitogen-activated protein kinase (MAPK) signaling pathway that subsequently leads to a variety of cellular changes, including proliferation, differentiation and motility. The regulation of growth factor signaling is complex, and various cell types respond differently to the same stimulus for reasons not entirely understood. The recent discovery in Drosophila of Sprouty (dSpry), an inhibitor of RTK-induced MAPK activation, provides clues to how these signals are regulated. In mammals, four orthologues of dSpry, Spry1-4, have been described, and in this review we discuss their functional characteristics. Mammalian Sprys, like dSpry, are ligand-induced feedback inhibitors of a number of growth factor receptors. In endothelial cells, upon fibroblast growth factor (FGF) receptor and vascular endothelial growth factor (VEGF) receptor activation, Sprys translocate to the plasma membrane and inhibit cell growth and proliferation. However, in epidermal growth factor (EGF)-stimulated cells, Sprys can enhance MAPK activation. In addition, Sprys have many binding partners, including different effectors of the MAPK activation pathway. The intersection point where Sprys interfere in the MAPK pathway as well as their interactions with other proteins may partly explain the dual, yet opposing roles, on growth factor-induced MAPK activation. Moreover, Sprys require tyrosine phosphorylation to interact with their binding partners, a prerequisite for their dual function. Hence, Sprys add another layer of complexity to the regulation of RTK-mediated signal transduction that begins to explain the variation in cellular responses to growth factors.

This publication was partially financed by Serono Foundation for the Advancement of Medical Science.

Part of this paper was originally presented at the 2^nd International Workshop on New Therapeutic Targets in Vascular Biology from February 6-9, 2003 in Geneva, Switzerland.

Keywords

Sprouty - growth factors - MAPK - angiogenesis - receptor tyrosine kinases

Full Text

References

References
1 Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 1996; 86 (03) 353-64.
2 Jones N, Iljin K, Dumont DJ. et al. Tie receptors: new modulators of angiogenic and lymph-angiogenic responses. Nat Rev Mol Cell Biol 2001; 2 (04) 257-67.
3 Hacohen N, Kramer S, Sutherland D. et al. Sprouty encodes a novel antagonist of FGF signaling that patterns apical branching of the Drosophila airways. Cell 1998; 92 (02) 253-63.
4 Affolter M, Bellusci S, Itoh N. et al. Tube or not tube: remodeling epithelial tissues by branching morphogenesis. Dev Cell 2003; 4 (01) 11-8.
5 Lubarsky B, Krasnow MA. Tube morphogenesis: making and shaping biological tubes. Cell 2003; 112 (01) 19-28.
6 Metzger RJ, Krasnow MA. Genetic control of branching morphogenesis. Science 1999; 284 5420 1635-9.
7 Casci T, Vinos J, Freeman M. Sprouty, an intracellular inhibitor of Ras signaling. Cell 1999; 96 (05) 655-65.
8 Kramer S, Okabe M, Hacohen N. et al. Sprouty: a common antagonist of FGF and EGF signaling pathways in Drosophila. Development 1999; 126 (11) 2515-25.
9 Reich A, Sapir A, Shilo B. Sprouty is a general inhibitor of receptor tyrosine kinase signaling. Development 1999; 126 (18) 4139-47.
10 Impagnatiello MA, Weitzer S, Gannon G. et al. Mammalian sprouty-1 and -2 are membrane-anchored phosphoprotein inhibitors of growth factor signaling in endothelial cells. J Cell Biol 2001; 152 (05) 1087-98.
11 Minowada G, Jarvis LA, Chi CL. et al. Vertebrate Sprouty genes are induced by FGF signaling and can cause chondrodysplasia when overexpressed. Development 1999; 126 (20) 4465-75.
12 de Maximy AA, Nakatake Y, Moncada S. et al. Cloning and expression pattern of a mouse homologue of drosophila sprouty in the mouse embryo. Mech Dev 1999; 81 1-2 213-6.
13 Tefft JD, Lee M, Smith S. et al. Conserved function of mSpry-2, a murine homolog of Drosophila sprouty, which negatively modulates respiratory organogenesis. Curr Biol 1999; 9 (04) 219-22.
14 Leeksma OC, Van Achterberg TA, Tsumura Y. et al. Human sprouty 4, a new ras antagonist on 5q31, interacts with the dual specificity kinase TESK1. Eur J Biochem 2002; 269 (10) 2546-56.
15 Wakioka T, Sasaki A, Kato R. et al. Spred is a Sprouty-related suppressor of Ras signalling. Nature 2001; 412 6847 647-51.
16 Kato R, Nonami A, Taketomi T. et al. Molecular cloning of mammalian Spred-3 which suppresses tyrosine kinase-mediated Erk activation. Biochem Biophys Res Commun 2003; 302 (04) 767-72.
17 Rechsteiner M, Rogers SW. PEST sequences and regulation by proteolysis. Trends Biochem Sci 1996; 21 (07) 267-71.
18 Gross I, Bassit B, Benezra M. et al. Mammalian sprouty proteins inhibit cell growth and differentiation by preventing ras activation. J Biol Chem 2001; 276 (49) 46460-8.
19 Lee SH, Schloss DJ, Jarvis L. et al. Inhibition of angiogenesis by a mouse sprouty protein. J Biol Chem 2001; 276 (06) 4128-33.
20 Glienke J, Fenten G, Seemann M. et al. Human SPRY2 inhibits FGF2 signalling by a secreted factor. Mech Dev 2000; 96 (01) 91-9.
21 Wong ES, Fong CW, Lim J. et al. Sprouty2 attenuates epidermal growth factor receptor ubiquitylation and endocytosis, and consequently enhances Ras/ERK signalling. Embo J 2002; 21 (18) 4796-808.
22 Sasaki A, Taketomi T, Wakioka T. et al. Identification of a dominant negative mutant of Sprouty that potentiates fibroblast growth factor- but not epidermal growth factor-induced ERK activation. J Biol Chem 2001; 276 (39) 36804-8.
23 Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell 2000; 103 (02) 211-25.
24 Hunter T. Signaling—2000 and beyond. Cell 2000; 100 (01) 113-27.
25 Tefft D, Lee M, Smith S. et al. mSprouty2 inhibits FGF10-activated MAP kinase by differentially binding to upstream target proteins. Am J Physiol Lung Cell Mol Physiol 2002; 283 (04) L700-6.
26 Hanafusa H, Torii S, Yasunaga T. et al. Sprouty1 and Sprouty2 provide a control mechanism for the Ras/MAPK signalling pathway. Nat Cell Biol 2002; 4 (11) 850-8.
27 Yusoff P, Lao DH, Ong SH. et al. Sprouty2 inhibits the Ras/MAP kinase pathway by inhibiting the activation of Raf. J Biol Chem 2002; 277 (05) 3195-201.
28 Egan JE, Hall AB, Yatsula BA. et al. The bimodal regulation of epidermal growth factor signaling by human Sprouty proteins. Proc Natl Acad Sci U S A 2002; 99 (09) 6041-6.
29 Wong ES, Lim J, Low BC. et al. Evidence for direct interaction between Sprouty and Cbl. J Biol Chem 2001; 276 (08) 5866-75.
30 Shtiegman K, Yarden Y. The role of ubiquity-lation in signaling by growth factors: implications to cancer. Semin Cancer Biol 2003; 13 (01) 29-40.
31 Thien CB, Langdon WY. Cbl: many adaptations to regulate protein tyrosine kinases. Nat Rev Mol Cell Biol 2001; 2 (04) 294-307.
32 Hall AB, Jura N, Da Silva J. et al. hSpry2 is targeted to the ubiquitin-dependent protea-some pathway by c-Cbl. Curr Biol 2003; 13 (04) 308-14.
33 Rubin C, Litvak V, Medvedovsky H. et al. Sprouty Fine-Tunes EGF Signaling through interlinked positive and negative feedback loops. Curr Biol 2003; 13 (04) 297-307.
34 Yigzaw Y, Poppleton HM, Sreejayan N. et al. Protein-tyrosine phosphatase-1B (PTP1B) mediates the anti-migratory actions of Sprouty. J Biol Chem 2003; 278 (01) 284-8.
35 Fielding CJ, Fielding PE. Relationship between cholesterol trafficking and signaling in rafts and caveolae. Biochim Biophys Acta 2003; 1610 (02) 219-28.
36 Yigzaw Y, Cartin L, Pierre S. et al. The C terminus of sprouty is important for modulation of cellular migration and proliferation. J Biol Chem 2001; 276 (25) 22742-7.
37 Lim J, Yusoff P, Wong ES. et al. The cysteine-rich sprouty translocation domain targets mitogen-activated protein kinase inhibitory proteins to phosphatidylinositol 4,5-bisphosphate in plasma membranes. Mol Cell Biol 2002; 22 (22) 7953-66.
38 Lim J, Wong ES, Ong SH. et al. Sprouty proteins are targeted to membrane ruffles upon growth factor receptor tyrosine kinase activation. Identification of a novel translocation domain. J Biol Chem 2000; 275 (42) 32837-45.