Abstract
Angiogenesis relies on endothelial cells properly processing signals from growth factors provided in both an autocrine and a paracrine manner. These mitogens bind to their cognate receptor tyrosine kinases (RTKs) on the cell surface, thereby activating a myriad of complex intracellular signaling pathways whose outputs include cell growth, migration, and morphogenesis. Understanding how these cascades are precisely controlled will provide insight into physiological and pathological angiogenesis. The Sprouty (Spry) family of proteins is a highly conserved group of negative feedback loop modulators of growth factor-mediated mitogen-activated protein kinase (MAPK) activation originally described in Drosophila. There are four mammalian orthologs (Spry1-4) whose modulation of RTK-induced signaling pathways is growth factor- and cell context-dependant. Endothelial cells are a group of highly differentiated cell types necessary for defining the mammalian vasculature. These cells respond to a plethora of growth factors and express all four Spry isoforms, thus highlighting the complexity that is required to form and maintain vessels in mammals. This review describes Spry functions in the context of endothelial biology and angiogenesis, and provides an update on Spry-interacting proteins and Spry mechanisms of action.
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Abbreviations
- Ang:
-
Angiopoietin
- c-Cbl:
-
Cellular homologue of Casitas B-lineage lymphoma proto-oncogene product
- EGF:
-
Epidermal growth factor
- EGFR:
-
EGF receptor
- eNOS:
-
Endothelial nitric oxide synthase
- ERK:
-
Extracellular signal-regulated kinase
- FGF:
-
Fibroblast growth factor
- FGFR:
-
FGF receptor
- GDNF:
-
Glial-derived neurotrophic factor
- Grb2:
-
Growth factor receptor-bound protein 2
- HMVEC:
-
Human microvascular endothelial cell
- Hrs:
-
Hepatocyte growth factor-regulated tyrosine kinase substrate
- HUVEC:
-
Human umbilical vein endothelial cell
- MAPK:
-
Mitogen-activated protein kinase
- MEK:
-
MAPK and ERK kinase
- Mnk1:
-
Mitogen-activated protein kinase-interacting kinase 1
- PDGF:
-
Platelet-derived growth factor
- PKC:
-
Protein kinase C
- PLC:
-
Phospholipase C
- PP2A:
-
Protein phosphatase 2A
- RBD:
-
Raf1-binding domain
- RTK:
-
Receptor tyrosine kinase
- Shp2:
-
SH2-domain-containing protein tyrosine phosphatase 2
- SIAH2:
-
Seven-in-Absentia Homolog 2
- SMC:
-
Smooth muscle cell
- Sos1:
-
Son of Sevenless 1
- Spry:
-
Sprouty
- Spred:
-
Spry-related proteins with Enabled/vasodilator-stimulated phosphoprotein homology 1 domain
- SPR:
-
Spry-related domain
- VEGF:
-
Vascular endothelial growth factor
- VEGFR:
-
VEGF receptor
References
Gschwind A, Fischer OM, Ullrich A (2004) The discovery of receptor tyrosine kinases: targets for cancer therapy. Nat Rev Cancer 4:361–370
Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70
Carmeliet P (2005) Angiogenesis in life, disease and medicine. Nature 438:932–936
Hanahan D, Folkman J (1996) Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86:353–364
Schlessinger J (2000) Cell signaling by receptor tyrosine kinases. Cell 103:211–225
Dor Y, Djonov V, Keshet E (2003) Making vascular networks in the adult: branching morphogenesis without a roadmap. Trends Cell Biol 13:131–136
Lu P, Sternlicht MD, Werb Z (2006) Comparative mechanisms of branching morphogenesis in diverse systems. J Mammary Gland Biol Neoplasia 11:213–228
Adams RH, Alitalo K (2007) Molecular regulation of angiogenesis and lymphangiogenesis. Nat Rev Mol Cell Biol 8:464–478
Ferrara N, Kerbel RS (2005) Angiogenesis as a therapeutic target. Nature 438:967–974
Dikic I, Giordano S (2003) Negative receptor signalling. Curr Opin Cell Biol 15:128–135
McKay MM, Morrison DK (2007) Integrating signals from RTKs to ERK/MAPK. Oncogene 26:3113–3121
Amit I, Citri A, Shay T et al (2007) A module of negative feedback regulators defines growth factor signaling. Nat Genet 39:503–512
Hacohen N, Kramer S, Sutherland D et al (1998) sprouty encodes a novel antagonist of FGF signaling that patterns apical branching of the Drosophila airways. Cell 92:253–263
Bundschu K, Walter U, Schuh K (2006) The VASP-Spred-Sprouty domain puzzle. J Biol Chem 281:36477–36481
Cabrita MA, Christofori G (2003) Sprouty proteins: antagonists of endothelial cell signaling and more. Thromb Haemost 90:586–590
Guy GR, Wong ES, Yusoff P et al (2003) Sprouty: how does the branch manager work? J Cell Sci 16:3061–3068
Kim HJ, Bar-Sagi D (2004) Modulation of signalling by Sprouty: a developing story. Nat Rev Mol Cell Biol 5:441–450
Mason JM, Morrison DJ, Basson MA et al (2006) Sprouty proteins: multifaceted negative-feedback regulators of receptor tyrosine kinase signaling. Trends Cell Biol 16:45–54
Bundschu K, Walter U, Schuh K (2007) Getting a first clue about SPRED functions. Bioessays 29:897–907
Leeksma OC, Van Achterberg TA, Tsumura Y et al (2002) Human sprouty 4, a new ras antagonist on 5q31, interacts with the dual specificity kinase TESK1. Eur J Biochem 269:2546–2556
Minowada G, Jarvis LA, Chi CL et al (1999) Vertebrate Sprouty genes are induced by FGF signaling and can cause chondrodysplasia when overexpressed. Development 126:4465–4475
Gross I, Bassit B, Benezra M et al (2001) Mammalian sprouty proteins inhibit cell growth and differentiation by preventing ras activation. J Biol Chem 276:46460–46468
Impagnatiello MA, Weitzer S, Gannon G et al (2001) Mammalian sprouty-1 and -2 are membrane-anchored phosphoprotein inhibitors of growth factor signaling in endothelial cells. J Cell Biol 152:1087–1098
Sasaki A, Taketomi T, Wakioka T et al (2001) Identification of a dominant negative mutant of Sprouty that potentiates fibroblast growth factor- but not epidermal growth factor-induced ERK activation. J Biol Chem 276:36804–36808
Lim J, Wong ES, Ong SH et al (2000) Sprouty proteins are targeted to membrane ruffles upon growth factor receptor tyrosine kinase activation. Identification of a novel translocation domain. J Biol Chem 275:32837–32845
Yigzaw Y, Cartin L, Pierre S et al (2001) The C terminus of sprouty is important for modulation of cellular migration and proliferation. J Biol Chem 276:22742–22747
Basson MA, Akbulut S, Watson-Johnson J et al (2005) Sprouty1 is a critical regulator of GDNF/RET-mediated kidney induction. Dev Cell 8:229–239
Gross I, Armant O, Benosman S et al (2007) Sprouty2 inhibits BDNF-induced signaling and modulates neuronal differentiation and survival. Cell Death Differ 14:1802–1812
Lee CC, Putnam AJ, Miranti CK et al (2004) Overexpression of sprouty 2 inhibits HGF/SF-mediated cell growth, invasion, migration, and cytokinesis. Oncogene 23:5193–5202
Choi H, Cho SY, Schwartz RH et al (2006) Dual effects of Sprouty1 on TCR signaling depending on the differentiation state of the T cell. J Immunol 176:6034–6045
Glienke J, Schmitt AO, Pilarsky C et al (2000) Differential gene expression by endothelial cells in distinct angiogenic states. Eur J Biochem 267:2820–2830
Bell SE, Mavila A, Salazar R et al (2001) 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. J Cell Sci 114:2755–2773
Jones N, Iljin K, Dumont DJ et al (2001) Tie receptors: new modulators of angiogenic and lymphangiogenic responses. Nat Rev Mol Cell Biol 2:257–267
Chi JT, Chang HY, Haraldsen G et al (2003) Endothelial cell diversity revealed by global expression profiling. Proc Natl Acad Sci U S A 100:10623–10628
Antoine M, Wirz W, Tag CG et al (2005) Expression pattern of fibroblast growth factors (FGFs), their receptors and antagonists in primary endothelial cells and vascular smooth muscle cells. Growth Factors 23:87–95
Paik JH, Kollipara R, Chu G et al (2007) FoxOs are lineage-restricted redundant tumor suppressors and regulate endothelial cell homeostasis. Cell 128:309–323
Dejana E, Taddei A, Randi AM (2007) Foxs and Ets in the transcriptional regulation of endothelial cell differentiation and angiogenesis. Biochim Biophys Acta 1775:298–312
Ding W, Bellusci S, Shi W et al (2003) Functional analysis of the human Sprouty2 gene promoter. Gene 322:175–185
Lee SH, Schloss DJ, Jarvis L et al (2001) Inhibition of angiogenesis by a mouse sprouty protein. J Biol Chem 276:4128–4133
Christofori G (2003) Split personalities: the agonistic antagonist Sprouty. Nat Cell Biol 5:377–379
Cabrita MA, Jaggi F, Widjaja SP et al (2006) A functional interaction between sprouty proteins and caveolin-1. J Biol Chem 281:29201–2912
Lao DH, Chandramouli S, Yusoff P et al (2006) 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. J Biol Chem 281:29993–30000
Ozaki K, Miyazaki S, Tanimura S et al (2005) Efficient suppression of FGF-2-induced ERK activation by the cooperative interaction among mammalian Sprouty isoforms. J Cell Sci 118:5861–5871
Egan JE, Hall AB, Yatsula BA et al (2002) The bimodal regulation of epidermal growth factor signaling by human Sprouty proteins. Proc Natl Acad Sci U S A 99:6041–6046
Fong CW, Leong HF, Wong ES et al (2003) Tyrosine phosphorylation of Sprouty2 enhances its interaction with c-Cbl and is crucial for its function. J Biol Chem 278:33456–33464
Rubin C, Litvak V, Medvedovsky H et al (2003) Sprouty fine-tunes EGF signaling through interlinked positive and negative feedback loops. Curr Biol 13:297–307
Schmelzle K, Kane S, Gridley S et al (2006) Temporal dynamics of tyrosine phosphorylation in insulin signaling. Diabetes 55:2171–2179
Mason JM, Morrison DJ, Bassit B et al (2004) Tyrosine phosphorylation of Sprouty proteins regulates their ability to inhibit growth factor signaling: a dual feedback loop. Mol Biol Cell 15:2176–2188
Hanafusa H, Torii S, Yasunaga T et al (2002) Sprouty1 and Sprouty2 provide a control mechanism for the Ras/MAPK signalling pathway. Nat Cell Biol 4:850–858
Hanafusa H, Torii S, Yasunaga T et al (2004) Shp2, an SH2-containing protein-tyrosine phosphatase, positively regulates receptor tyrosine kinase signaling by dephosphorylating and inactivating the inhibitor Sprouty. J Biol Chem 279:22992–22995
Jarvis LA, Toering SJ, Simon MA et al (2006) Sprouty proteins are in vivo targets of Corkscrew/SHP-2 tyrosine phosphatases. Development 133:1133–1142
Li X, Brunton VG, Burgar HR et al (2004) FRS2-dependent SRC activation is required for fibroblast growth factor receptor-induced phosphorylation of Sprouty and suppression of ERK activity. J Cell Sci 117:6007–6017
Presta M, Dell’Era P, Mitola S et al (2005) Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis. Cytokine Growth Factor Rev 16:159–178
Casci T, Vinos J, Freeman M (1999) Sprouty, an intracellular inhibitor of Ras signaling. Cell 96:655–665
Martinez N, Garcia-Dominguez CA, Domingo B et al (2007) Sprouty2 binds Grb2 at two different proline-rich regions, and the mechanism of ERK inhibition is independent of this interaction. Cell Signal 19:2277–2285
Rubin C, Zwang Y, Vaisman N et al (2005) Phosphorylation of carboxyl-terminal tyrosines modulates the specificity of Sprouty-2 inhibition of different signaling pathways. J Biol Chem 280:9735–9744
Lao DH, Yusoff P, Chandramouli S et al (2007) Direct binding of PP2A to Sprouty2 and phosphorylation changes are a prerequisite for ERK inhibition downstream of fibroblast growth factor receptor stimulation. J Biol Chem 282:9117–9126
Amin DN, Hida K, Bielenberg DR et al (2006) Tumor endothelial cells express epidermal growth factor receptor (EGFR) but not ErbB3 and are responsive to EGF and to EGFR kinase inhibitors. Cancer Res 66:2173–2180
Sini P, Wyder L, Schnell C et al (2005) The antitumor and antiangiogenic activity of vascular endothelial growth factor receptor inhibition is potentiated by ErbB1 blockade. Clin Cancer Res 11:4521–4532
van Cruijsen H, Giaccone G, Hoekman K (2005) Epidermal growth factor receptor and angiogenesis: Opportunities for combined anticancer strategies. Int J Cancer 117:883–888
Wong ES, Fong CW, Lim J et al (2002) Sprouty2 attenuates epidermal growth factor receptor ubiquitylation and endocytosis, and consequently enhances Ras/ERK signalling. EMBO J 21:4796–4808
Wong ES, Lim J, Low BC et al (2001) Evidence for direct interaction between Sprouty and Cbl. J Biol Chem 276:5866–5875
Haglund K, Schmidt MH, Wong ES et al (2005) Sprouty2 acts at the Cbl/CIN85 interface to inhibit epidermal growth factor receptor downregulation. EMBO Rep 6:635–641
Kim HJ, Taylor LJ, Bar-Sagi D (2007) Spatial regulation of EGFR signaling by Sprouty2. Curr Biol 17:455–461
Coultas L, Chawengsaksophak K, Rossant J (2005) Endothelial cells and VEGF in vascular development. Nature 438:937–945
Takahashi T, Yamaguchi S, Chida K et al (2001) A single autophosphorylation site on KDR/Flk-1 is essential for VEGF-A-dependent activation of PLC-gamma and DNA synthesis in vascular endothelial cells. EMBO J 20:2768–2778
Sasaki A, Taketomi T, Kato R et al (2003) Mammalian Sprouty4 suppresses Ras-independent ERK activation by binding to Raf1. Nat Cell Biol 5:427–432
Parton RG, Simons K (2007) The multiple faces of caveolae. Nat Rev Mol Cell Biol 8:185–194
Bauer PM, Yu J, Chen Y et al (2005) Endothelial-specific expression of caveolin-1 impairs microvascular permeability and angiogenesis. Proc Natl Acad Sci U S A 102:204–209
Lin MI, Yu J, Murata T et al (2007) Caveolin-1-deficient mice have increased tumor microvascular permeability, angiogenesis, and growth. Cancer Res 67:2849–2856
Liu J, Wang XB, Park DS et al (2002) Caveolin-1 expression enhances endothelial capillary tubule formation. J Biol Chem 277:10661–10668
Woodman SE, Ashton AW, Schubert W et al (2003) Caveolin-1 knockout mice show an impaired angiogenic response to exogenous stimuli. Am J Pathol 162:2059–2068
Galbiati F, Volonte D, Engelman JA et al (1998) Targeted downregulation of caveolin-1 is sufficient to drive cell transformation and hyperactivate the p42/44 MAP kinase cascade. EMBO J 17:6633–6648
Kajita M, Ikeda W, Tamaru Y et al (2007) Regulation of platelet-derived growth factor-induced Ras signaling by poliovirus receptor Necl-5 and negative growth regulator Sprouty2. Genes Cells 12:345–357
Sakisaka T, Ikeda W, Ogita H et al (2007) The roles of nectins in cell adhesions: cooperation with other cell adhesion molecules and growth factor receptors. Curr Opin Cell Biol 19:593–602
Couderc T, Barzu T, Horaud F et al (1990) Poliovirus permissivity and specific receptor expression on human endothelial cells. Virology 174:95–102
Chandramouli S, Yu CY, Yusoff P et al (2008) Tesk1 interacts with sprouty2 to abrogate its inhibition of ERK phosphorylation downstream of receptor tyrosine kinase signaling. J Biol Chem 283:1679–1691
Tsumura Y, Toshima J, Leeksma OC et al (2005) Sprouty-4 negatively regulates cell spreading by inhibiting the kinase activity of testicular protein kinase. Biochem J 387:627–637
Ozaki K, Kadomoto R, Asato K et al (2001) ERK pathway positively regulates the expression of Sprouty genes. Biochem Biophys Res Commun 285:1084–1088
Hall AB, Jura N, DaSilva J et al (2003) hSpry2 is targeted to the ubiquitin-dependent proteasome pathway by c-Cbl. Curr Biol 13:308–314
Rubin C, Gur G, Yarden Y (2005) Negative regulation of receptor tyrosine kinases: unexpected links to c-Cbl and receptor ubiquitylation. Cell Res 15:66–71
DaSilva J, Xu L, Kim HJ et al (2006) Regulation of sprouty stability by Mnk1-dependent phosphorylation. Mol Cell Biol 26:1898–1907
Ding W, Shi W, Bellusci S et al (2007) Sprouty2 downregulation plays a pivotal role in mediating crosstalk between TGF-beta1 signaling and EGF as well as FGF receptor tyrosine kinase-ERK pathways in mesenchymal cells. J Cell Physiol 212:796–806
Nadeau RJ, Toher JL, Yang X et al (2007) Regulation of Sprouty2 stability by mammalian Seven-in-Absentia homolog 2. J Cell Biochem 100:151–160
Jain RK (2003) Molecular regulation of vessel maturation. Nat Med 9:685–693
Wu X, Alexander PB, He Y et al (2005) Mammalian sprouty proteins assemble into large monodisperse particles having the properties of intracellular nanobatteries. Proc Natl Acad Sci U S A 102:14058–14062
Wingrove JA, O’Farrell PH (1999) Nitric oxide contributes to behavioral, cellular, and developmental responses to low oxygen in Drosophila. Cell 98:105–114
Ying L, Hofseth LJ (2007) An emerging role for endothelial nitric oxide synthase in chronic inflammation and cancer. Cancer Res 67:1407–1410
Minshall RD, Sessa WC, Stan RV et al (2003) Caveolin regulation of endothelial function. Am J Physiol Lung Cell Mol Physiol 285:L1179–L1183
Basson MA, Watson-Johnson J, Shakya R et al (2006) Branching morphogenesis of the ureteric epithelium during kidney development is coordinated by the opposing functions of GDNF and Sprouty1. Dev Biol 299:466–477
Shim K, Minowada G, Coling DE et al (2005) Sprouty2, a mouse deafness gene, regulates cell fate decisions in the auditory sensory epithelium by antagonizing FGF signaling. Dev Cell 8:553–564
Taketomi T, Yoshiga D, Taniguchi K et al (2005) Loss of mammalian Sprouty2 leads to enteric neuronal hyperplasia and esophageal achalasia. Nat Neurosci 8:855–857
Klein OD, Minowada G, Peterkova R et al (2006) Sprouty genes control diastema tooth development via bidirectional antagonism of epithelial-mesenchymal FGF signaling. Dev Cell 11:181–190
Taniguchi K, Ayada T, Ichiyama K et al (2007) Sprouty2 and Sprouty4 are essential for embryonic morphogenesis and regulation of FGF signaling. Biochem Biophys Res Commun 352:896–902
Sivak JM, Petersen LF, Amaya E (2005) FGF signal interpretation is directed by Sprouty and Spred proteins during mesoderm formation. Dev Cell 8:689–701
Taniguchi K, Kohno R, Ayada T et al (2007) Spreds are essential for embryonic lymphangiogenesis by regulating vascular endothelial growth factor receptor 3 signaling. Mol Cell Biol 27:4541–4550
Acknowledgments
The authors are grateful to Drs. Imke Albrecht, Anna Fantozzi, and Tibor Schomber for critically reading the manuscript. We apologize to all colleagues whose important work we could not cite due to space limitations. M.A.C. was initially supported by a post-doctoral fellowship from the International Agency for Research on Cancer (IARC–WHO). Research in the laboratory of the authors is supported by the Swiss National Science Foundation, Swiss Bridge Award, Krebsliga Beider Basel, Swiss Cancer League, EU-FP6 Framework programmes LYMPHANGIOGENOMICS LSHG-CT-2004-503573 and BRECOSM LSHC-CT-2004-503224, SNF-NCCR Moleculary Oncology, and Novartis Pharma Inc.
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Cabrita, M.A., Christofori, G. Sprouty proteins, masterminds of receptor tyrosine kinase signaling. Angiogenesis 11, 53–62 (2008). https://doi.org/10.1007/s10456-008-9089-1
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DOI: https://doi.org/10.1007/s10456-008-9089-1