SPRY2 explained

Sprouty homolog 2 (Drosophila), also known as SPRY2, is a protein which in humans is encoded by the SPRY2 gene.^[1]

Function

This gene encodes a protein belonging to the sprouty family. The encoded protein contains a carboxyl-terminal cysteine-rich domain essential for the inhibitory activity on receptor tyrosine kinase signaling proteins and is required for growth factor stimulated translocation of the protein to membrane ruffles. In primary dermal endothelial cells this gene is transiently upregulated in response to fibroblast growth factor two. This protein is indirectly involved in the non-cell autonomous inhibitory effect on fibroblast growth factor two signaling. The protein interacts with Cas-Br-M (murine) ectropic retroviral transforming sequence, and can function as a bimodal regulator of epidermal growth factor receptor/mitogen-activated protein kinase signaling. This protein may play a role in alveoli branching during lung development as shown by a similar mouse protein.^[2]

SPRY2 is a negative feedback regulator of multiple receptor tyrosine kinases (RTKs) including receptors for fibroblast growth factor (FGF), epidermal growth factor (EGF),^[3] and hepatocyte growth factor (HGF).^[4] Antagonization of growth factor mediated pathways, cell migration, and cellular differentiation occurs through the ERK pathway.^[3] Spry2 can also enhance EGFR signaling by sequestering CBL. Spry gene expression has been reported silenced or repressed in cancer of the breast, liver, lung, prostate,^[3] and in lymphoma.^[5] Human spry2 expression is localized to the microtubules in unstimulated cells.^[6] All sprouty isoforms inhibit the ERK pathway by themselves, but can also form heterodimers and homodimers which have enhanced inhibition.^[6]

Interactions

SPRY2 has been shown to interact with Cbl gene.^{[7] [8] [9]}

See also

• SPRED1 gene
• Neurofibromin 1
• SPRY1

Further reading

• Hacohen N, Kramer S, Sutherland D, Hiromi Y, Krasnow MA . sprouty encodes a novel antagonist of FGF signaling that patterns apical branching of the Drosophila airways . Cell . 92 . 2 . 253–63 . January 1998 . 9458049 . 10.1016/S0092-8674(00)80919-8 . free .
• Lim J, Wong ES, Ong SH, Yusoff P, Low BC, Guy GR . Sprouty proteins are targeted to membrane ruffles upon growth factor receptor tyrosine kinase activation. Identification of a novel translocation domain . The Journal of Biological Chemistry . 275 . 42 . 32837–45 . October 2000 . 10887178 . 10.1074/jbc.M002156200 . free .
• Glienke J, Fenten G, Seemann M, Sturz A, Thierauch KH . Human SPRY2 inhibits FGF2 signalling by a secreted factor . Mechanisms of Development . 96 . 1 . 91–9 . August 2000 . 10940627 . 10.1016/S0925-4773(00)00378-6 . free .
• Wong ES, Lim J, Low BC, Chen Q, Guy GR . Evidence for direct interaction between Sprouty and Cbl . The Journal of Biological Chemistry . 276 . 8 . 5866–75 . February 2001 . 11053437 . 10.1074/jbc.M006945200 . free.
• Hartley JL, Temple GF, Brasch MA . DNA cloning using in vitro site-specific recombination . Genome Research . 10 . 11 . 1788–95 . November 2000 . 11076863 . 310948 . 10.1101/gr.143000 .
• Wiemann S, Weil B, Wellenreuther R, Gassenhuber J, Glassl S, Ansorge W, Böcher M, Blöcker H, Bauersachs S, Blum H, Lauber J, Düsterhöft A, Beyer A, Köhrer K, Strack N, Mewes HW, Ottenwälder B, Obermaier B, Tampe J, Heubner D, Wambutt R, Korn B, Klein M, Poustka A . Toward a catalog of human genes and proteins: sequencing and analysis of 500 novel complete protein coding human cDNAs . Genome Research . 11 . 3 . 422–35 . March 2001 . 11230166 . 311072 . 10.1101/gr.GR1547R .
• Yusoff P, Lao DH, Ong SH, Wong ES, Lim J, Lo TL, Leong HF, Fong CW, Guy GR . Sprouty2 inhibits the Ras/MAP kinase pathway by inhibiting the activation of Raf . The Journal of Biological Chemistry . 277 . 5 . 3195–201 . February 2002 . 11698404 . 10.1074/jbc.M108368200 . free .
• Egan JE, Hall AB, Yatsula BA, Bar-Sagi D . The bimodal regulation of epidermal growth factor signaling by human Sprouty proteins . Proceedings of the National Academy of Sciences of the United States of America . 99 . 9 . 6041–6 . April 2002 . 11983899 . 122898 . 10.1073/pnas.052090899 . 2002PNAS...99.6041E . free .
• Wong ES, Fong CW, Lim J, Yusoff P, Low BC, Langdon WY, Guy GR . Sprouty2 attenuates epidermal growth factor receptor ubiquitylation and endocytosis, and consequently enhances Ras/ERK signalling . The EMBO Journal . 21 . 18 . 4796–808 . September 2002 . 12234920 . 126289 . 10.1093/emboj/cdf493 .
• Lim J, Yusoff P, Wong ES, Chandramouli S, Lao DH, Fong CW, Guy GR . The cysteine-rich sprouty translocation domain targets mitogen-activated protein kinase inhibitory proteins to phosphatidylinositol 4,5-bisphosphate in plasma membranes . Molecular and Cellular Biology . 22 . 22 . 7953–66 . November 2002 . 12391162 . 134720 . 10.1128/MCB.22.22.7953-7966.2002 .
• Hanafusa H, Torii S, Yasunaga T, Nishida E . Sprouty1 and Sprouty2 provide a control mechanism for the Ras/MAPK signalling pathway . Nature Cell Biology . 4 . 11 . 850–8 . November 2002 . 12402043 . 10.1038/ncb867 . 31064800 .
• Yigzaw Y, Poppleton HM, Sreejayan N, Hassid A, Patel TB . Protein-tyrosine phosphatase-1B (PTP1B) mediates the anti-migratory actions of Sprouty . The Journal of Biological Chemistry . 278 . 1 . 284–8 . January 2003 . 12414790 . 10.1074/jbc.M210359200 . free .
• Hall AB, Jura N, DaSilva J, Jang YJ, Gong D, Bar-Sagi D . hSpry2 is targeted to the ubiquitin-dependent proteasome pathway by c-Cbl . Current Biology . 13 . 4 . 308–14 . February 2003 . 12593796 . 10.1016/S0960-9822(03)00086-1 . free .
• Sasaki A, Taketomi T, Kato R, Saeki K, Nonami A, Sasaki M, Kuriyama M, Saito N, Shibuya M, Yoshimura A . Mammalian Sprouty4 suppresses Ras-independent ERK activation by binding to Raf1 . Nature Cell Biology . 5 . 5 . 427–32 . May 2003 . 12717443 . 10.1038/ncb978 . 33846459 .
• Fong CW, Leong HF, Wong ES, Lim J, Yusoff P, Guy GR . Tyrosine phosphorylation of Sprouty2 enhances its interaction with c-Cbl and is crucial for its function . The Journal of Biological Chemistry . 278 . 35 . 33456–64 . August 2003 . 12815057 . 10.1074/jbc.M301317200 . free .
• Hanafusa H, Torii S, Yasunaga T, Matsumoto K, Nishida E . Shp2, an SH2-containing protein-tyrosine phosphatase, positively regulates receptor tyrosine kinase signaling by dephosphorylating and inactivating the inhibitor Sprouty . The Journal of Biological Chemistry . 279 . 22 . 22992–5 . May 2004 . 15031289 . 10.1074/jbc.M312498200 . free .
• Lee CC, Putnam AJ, Miranti CK, Gustafson M, Wang LM, Vande Woude GF, Gao CF . Overexpression of sprouty 2 inhibits HGF/SF-mediated cell growth, invasion, migration, and cytokinesis . Oncogene . 23 . 30 . 5193–202 . July 2004 . 15122328 . 10.1038/sj.onc.1207646 . 56279 .
• Chi L, Zhang S, Lin Y, Prunskaite-Hyyryläinen R, Vuolteenaho R, Itäranta P, Vainio S . Sprouty proteins regulate ureteric branching by coordinating reciprocal epithelial Wnt11, mesenchymal Gdnf and stromal Fgf7 signalling during kidney development . Development . 131 . 14 . 3345–56 . July 2004 . 15201220 . 10.1242/dev.01200 . 6471981 .

Notes and References

1. Hacohen N, Kramer S, Sutherland D, Hiromi Y, Krasnow MA . sprouty encodes a novel antagonist of FGF signaling that patterns apical branching of the Drosophila airways . Cell . 92 . 2 . 253–63 . January 1998 . 9458049 . 10.1016/S0092-8674(00)80919-8 . free .
2. Web site: Entrez Gene: SPRY2 sprouty homolog 2 (Drosophila).
3. Frank MJ, Dawson DW, Bensinger SJ, Hong JS, Knosp WM, Xu L, Balatoni CE, Allen EL, Shen RR, Bar-Sagi D, Martin GR, Teitell MA . Expression of sprouty2 inhibits B-cell proliferation and is epigenetically silenced in mouse and human B-cell lymphomas . Blood . 113 . 11 . 2478–87 . March 2009 . 19147787 . 2656273 . 10.1182/blood-2008-05-156943 .
4. Lee CC, Putnam AJ, Miranti CK, Gustafson M, Wang LM, Vande Woude GF, Gao CF . Overexpression of sprouty 2 inhibits HGF/SF-mediated cell growth, invasion, migration, and cytokinesis . Oncogene . 23 . 30 . 5193–202 . July 2004 . 15122328 . 10.1038/sj.onc.1207646 . 56279 .
5. Sánchez A, Setién F, Martinez N, Oliva JL, Herranz M, Fraga MF, Alaminos M, Esteller M, Rojas JM . Epigenetic inactivation of the ERK inhibitor Spry2 in B-cell diffuse lymphomas . Oncogene . 27 . 36 . 4969–72 . August 2008 . 18427547 . 10.1038/onc.2008.129 . 19450976 .
6. Bundschu K, Walter U, Schuh K . The VASP-Spred-Sprouty domain puzzle . The Journal of Biological Chemistry . 281 . 48 . 36477–81 . December 2006 . 16987806 . 10.1074/jbc.R600023200 . free .
7. Wong ES, Lim J, Low BC, Chen Q, Guy GR . Evidence for direct interaction between Sprouty and Cbl . The Journal of Biological Chemistry . 276 . 8 . 5866–75 . February 2001 . 11053437 . 10.1074/jbc.M006945200 . free.
8. Wong ES, Fong CW, Lim J, Yusoff P, Low BC, Langdon WY, Guy GR . Sprouty2 attenuates epidermal growth factor receptor ubiquitylation and endocytosis, and consequently enhances Ras/ERK signalling . The EMBO Journal . 21 . 18 . 4796–808 . September 2002 . 12234920 . 126289 . 10.1093/emboj/cdf493 .
9. Ng C, Jackson RA, Buschdorf JP, Sun Q, Guy GR, Sivaraman J . Structural basis for a novel intrapeptidyl H-bond and reverse binding of c-Cbl-TKB domain substrates . The EMBO Journal . 27 . 5 . 804–16 . March 2008 . 18273061 . 2265755 . 10.1038/emboj.2008.18 .