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Gene Review

SPRY2  -  sprouty homolog 2 (Drosophila)

Homo sapiens

Synonyms: Protein sprouty homolog 2, Spry-2, hSPRY2
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Disease relevance of SPRY2

  • Ectopic SPRY2 expression led to postnatal death resulting from kidney failure, manifested as unilateral agenesis, lobularization of the organ or reduction in organ size because of inhibition of ureteric branching [1].
  • Epigenetic inactivation of the human sprouty2 (hSPRY2) homologue in prostate cancer [2].
  • We observed downregulated Spry2 expression in invasive CaP cell lines and high-grade clinical CaP (compared to benign prostatic hyperplasia (BPH) and well-differentiated tumours, P=0.041) [2].
  • Human Sprouty2 (hSpry2) binds the catalytic RING Finger of Casitas B-lineage lymphoma (c-Cbl), an E3 ubiquitin ligase that has been identified to target EGFR degradation [3].

High impact information on SPRY2

  • Here we show that after stimulation by growth factors Spry1 and Spry2 translocate to the plasma membrane and become phosphorylated on a conserved tyrosine [4].
  • Correlative evidence showed the failure of hSpry2DeltaN11 and mSpry4, both deficient in c-Cbl binding, to instigate these effects. hSpry2 interacts specifically with the c-Cbl RING finger domain and displaces UbcH7 from its binding site on the E3 ligase [5].
  • We conclude that hSpry2 potentiates EGFR signalling by specifically intercepting c-Cbl-mediated effects on receptor down-regulation [5].
  • Ectopically expressed full-length hSpry1 and hSpry2 induce the potentiation of EGFR-mediated mitogen-activated protein (MAP) kinase activation [6].
  • In contrast, truncation mutants of hSpry1 and hSpry2 containing the highly conserved carboxyl-terminal cysteine-rich domain inhibit EGF-induced MAP kinase activation [6].

Biological context of SPRY2

  • We showed that human SPRY2 inhibits cell growth and migration in response to serum and several growth factors [7].
  • In contrast to a previous report, no hypermethylation was found to accompany down-regulation of SPRY2 in cancer tissues and cell lines [8].
  • Previous studies have shown that growth factor stimulation induces the proteolytic degradation of hSpry2 by stimulating tyrosine phosphorylation on hSpry2, which in turn promotes c-Cbl binding and polyubiquitination [9].
  • Our data show that the deletion of either of these two regions in hSPRY2 abrogates its ability to modulate cell migration in response to different growth factors and proliferation in response to serum [10].
  • Here we have demonstrated that hSPRY2 increases the amount of the tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and decreases its phosphorylation [11].

Anatomical context of SPRY2

  • We show that in primary human dermal endothelial cells (MVEC) SPRY2 mRNA is transiently upregulated in response to FGF2 [12].
  • In this communication, using HeLa cells, we have examined the possibility that human Sprouty 2 (hSPRY2) mediates its anti-migratory actions by modulating the activity or intracellular localization of protein-tyrosine phosphatases [13].
  • In unstimulated cells, the Spry proteins were distributed throughout the cytosol except for human Sprouty2 (hSpry2), which, although generally located in the cytosol, co-localized with microtubules [14].
  • Previously, two C-terminal domains on hSPRY2, which are necessary for its colocalization with microtubules (residues 123-177) or translocation to membrane ruffles (residues 178-194), have been identified (Lim, J., Wong, E. S., Ong, S. H., Yusoff, P., Low, B. C., and Guy, G. R. (2000) J. Biol. Chem. 275, 32837-32845) [10].
  • In the context of fibroblast growth factor (FGF) signaling, Sprouty2 (Spry2) is the most profound inhibitor of the Ras/ERK pathway as compared with other Spry isoforms [15].

Associations of SPRY2 with chemical compounds


Physical interactions of SPRY2

  • However, SPRY2 protein binds the intracellular adaptor protein GRB2, indicating an intracellular localization [12].
  • SRC forms a complex with hSpry2 and this interaction is enhanced by hSpry2 phosphorylation [16].
  • A hSpry2 mutant (Y55F) that did not exhibit an enhanced binding with c-Cbl failed to retain EGF receptors on the cell surface [17].
  • Furthermore, individually mutating hSpry2 residues 52-59 to alanine indicated a tight correlation between their affinity for c-Cbl binding and their inhibition of ERK2 activity in the FGFR pathway [17].
  • Furthermore, we show that Spry2 interacts with Raf-1 in a glutathione-S-transferase pulldown assay and that this interaction may involve multiple sites [18].

Enzymatic interactions of SPRY2

  • We have found that hSpry2 is ubiquitinated by c-Cbl in an EGF-dependent manner [19].
  • In this study it is demonstrated that hSpry2 is tyrosine-phosphorylated upon stimulation by either FGFR or EGF and subsequently binds endogenous c-Cbl with high affinity [17].

Regulatory relationships of SPRY2


Other interactions of SPRY2

  • These results indicate that hSpry2 can function both as a negative and positive regulator of EGFR-mediated MAP kinase signaling in a domain-dependent fashion [6].
  • Interestingly, neither WT nor C215S mutant forms of PTP1B modulated the anti-mitogenic actions of hSPRY2 [13].
  • The PXXPXR motif is cryptic in unstimulated cells, and it is postulated that Spry2 undergoes a conformational change following FGFR stimulation, enabling the subsequent interaction with Grb2 [21].
  • We show by yeast two-hybrid analysis that the N-terminal domain of Spry2 and the ring finger domain of SIAH2 mediated this interaction [22].
  • Conversely, enhancement of serine phosphorylation achieved through either the inhibition of cellular phosphatases or the expression of active Mnk1 results in the stabilization of hSpry2 [9].

Analytical, diagnostic and therapeutic context of SPRY2

  • The optimal translocation domain was identified by deletion and immunofluorescence analysis to be a highly conserved 105-amino acid domain in the C-terminal half of the hSpry2 protein [14].
  • The activation of Spry2 appears to be linked to sequences in the N-terminal half of the protein and correlated with a bandshifting seen on SDS-PAGE [15].
  • Measured in an electric cell-substrate impedance sensing biosensor, cell movement is restricted, because Spry2 dramatically facilitates cell attachment and spreading by enhancing focal adhesions and increasing stress fibers [23].


  1. Sprouty proteins regulate ureteric branching by coordinating reciprocal epithelial Wnt11, mesenchymal Gdnf and stromal Fgf7 signalling during kidney development. Chi, L., Zhang, S., Lin, Y., Prunskaite-Hyyryläinen, R., Vuolteenaho, R., Itäranta, P., Vainio, S. Development (2004) [Pubmed]
  2. Epigenetic inactivation of the human sprouty2 (hSPRY2) homologue in prostate cancer. McKie, A.B., Douglas, D.A., Olijslagers, S., Graham, J., Omar, M.M., Heer, R., Gnanapragasam, V.J., Robson, C.N., Leung, H.Y. Oncogene (2005) [Pubmed]
  3. Regulator of epidermal growth factor signaling: Sprouty. Wong, E.S., Guy, G.R. Methods Mol. Biol. (2006) [Pubmed]
  4. Sprouty1 and Sprouty2 provide a control mechanism for the Ras/MAPK signalling pathway. Hanafusa, H., Torii, S., Yasunaga, T., Nishida, E. Nat. Cell Biol. (2002) [Pubmed]
  5. Sprouty2 attenuates epidermal growth factor receptor ubiquitylation and endocytosis, and consequently enhances Ras/ERK signalling. Wong, E.S., Fong, C.W., Lim, J., Yusoff, P., Low, B.C., Langdon, W.Y., Guy, G.R. EMBO J. (2002) [Pubmed]
  6. The bimodal regulation of epidermal growth factor signaling by human Sprouty proteins. Egan, J.E., Hall, A.B., Yatsula, B.A., Bar-Sagi, D. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  7. Sprouty regulates cell migration by inhibiting the activation of Rac1 GTPase. Poppleton, H.M., Edwin, F., Jaggar, L., Ray, R., Johnson, L.R., Patel, T.B. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
  8. Concomitant down-regulation of SPRY1 and SPRY2 in prostate carcinoma. Fritzsche, S., Kenzelmann, M., Hoffmann, M.J., Müller, M., Engers, R., Gröne, H.J., Schulz, W.A. Endocr. Relat. Cancer (2006) [Pubmed]
  9. Regulation of sprouty stability by Mnk1-dependent phosphorylation. DaSilva, J., Xu, L., Kim, H.J., Miller, W.T., Bar-Sagi, D. Mol. Cell. Biol. (2006) [Pubmed]
  10. The C terminus of sprouty is important for modulation of cellular migration and proliferation. Yigzaw, Y., Cartin, L., Pierre, S., Scholich, K., Patel, T.B. J. Biol. Chem. (2001) [Pubmed]
  11. The tumor suppressor PTEN is necessary for human Sprouty 2-mediated inhibition of cell proliferation. Edwin, F., Singh, R., Endersby, R., Baker, S.J., Patel, T.B. J. Biol. Chem. (2006) [Pubmed]
  12. Human SPRY2 inhibits FGF2 signalling by a secreted factor. Glienke, J., Fenten, G., Seemann, M., Sturz, A., Thierauch, K.H. Mech. Dev. (2000) [Pubmed]
  13. Protein-tyrosine phosphatase-1B (PTP1B) mediates the anti-migratory actions of Sprouty. Yigzaw, Y., Poppleton, H.M., Sreejayan, N., Hassid, A., Patel, T.B. J. Biol. Chem. (2003) [Pubmed]
  14. Sprouty proteins are targeted to membrane ruffles upon growth factor receptor tyrosine kinase activation. Identification of a novel translocation domain. Lim, J., Wong, E.S., Ong, S.H., Yusoff, P., Low, B.C., Guy, G.R. J. Biol. Chem. (2000) [Pubmed]
  15. Direct Binding of PP2A to Sprouty2 and Phosphorylation Changes Are a Prerequisite for ERK Inhibition Downstream of Fibroblast Growth Factor Receptor Stimulation. Lao, D.H., Yusoff, P., Chandramouli, S., Philp, R.J., Fong, C.W., Jackson, R.A., Saw, T.Y., Yu, C.Y., Guy, G.R. J. Biol. Chem. (2007) [Pubmed]
  16. FRS2-dependent SRC activation is required for fibroblast growth factor receptor-induced phosphorylation of Sprouty and suppression of ERK activity. Li, X., Brunton, V.G., Burgar, H.R., Wheldon, L.M., Heath, J.K. J. Cell. Sci. (2004) [Pubmed]
  17. Tyrosine phosphorylation of Sprouty2 enhances its interaction with c-Cbl and is crucial for its function. Fong, C.W., Leong, H.F., Wong, E.S., Lim, J., Yusoff, P., Guy, G.R. J. Biol. Chem. (2003) [Pubmed]
  18. Sprouty genes are expressed in osteoblasts and inhibit fibroblast growth factor-mediated osteoblast responses. Yang, X., Webster, J.B., Kovalenko, D., Nadeau, R.J., Zubanova, O., Chen, P.Y., Friesel, R. Calcif. Tissue Int. (2006) [Pubmed]
  19. hSpry2 is targeted to the ubiquitin-dependent proteasome pathway by c-Cbl. Hall, A.B., Jura, N., DaSilva, J., Jang, Y.J., Gong, D., Bar-Sagi, D. Curr. Biol. (2003) [Pubmed]
  20. Human placental Hofbauer cells express sprouty proteins: a possible modulating mechanism of villous branching. Anteby, E.Y., Natanson-Yaron, S., Greenfield, C., Goldman-Wohl, D., Haimov-Kochman, R., Holzer, H., Yagel, S. Placenta (2005) [Pubmed]
  21. 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. Lao, D.H., Chandramouli, S., Yusoff, P., Fong, C.W., Saw, T.Y., Tai, L.P., Yu, C.Y., Leong, H.F., Guy, G.R. J. Biol. Chem. (2006) [Pubmed]
  22. Regulation of Sprouty2 stability by mammalian Seven-in-Absentia homolog 2. Nadeau, R.J., Toher, J.L., Yang, X., Kovalenko, D., Friesel, R. J. Cell. Biochem. (2007) [Pubmed]
  23. Overexpression of sprouty 2 inhibits HGF/SF-mediated cell growth, invasion, migration, and cytokinesis. Lee, C.C., Putnam, A.J., Miranti, C.K., Gustafson, M., Wang, L.M., Vande Woude, G.F., Gao, C.F. Oncogene (2004) [Pubmed]
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