SPRY2

Sprouty RTK signaling antagonist 2
Rendering based on PDB 3BUM​.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 3BUM​, 3OB1​
Identifiers
Symbols	SPRY2 ; hSPRY2
External IDs	OMIM: 602466 MGI: 1345138 HomoloGene: 4267 GeneCards: SPRY2 Gene
Gene ontology Molecular function • protein binding • protein kinase binding • protein serine/threonine kinase inhibitor activity • protein serine/threonine kinase activator activity Cellular component • cytosol • microtubule • plasma membrane • microtubule cytoskeleton • ruffle membrane Biological process • establishment of mitotic spindle orientation • epidermal growth factor receptor signaling pathway • sensory perception of sound • negative regulation of cell proliferation • fibroblast growth factor receptor signaling pathway • positive regulation of gene expression • negative regulation of peptidyl-threonine phosphorylation • positive regulation of peptidyl-serine phosphorylation • negative regulation of GTPase activity • negative regulation of fibroblast growth factor receptor signaling pathway • negative regulation of epidermal growth factor receptor signaling pathway • inner ear morphogenesis • negative regulation of apoptotic process • negative regulation of MAP kinase activity • cell fate commitment • regulation of cell differentiation • negative regulation of Ras protein signal transduction • negative regulation of neurotrophin TRK receptor signaling pathway • positive regulation of protein kinase B signaling • lung growth • bud elongation involved in lung branching • negative regulation of ERK1 and ERK2 cascade • positive regulation of ERK1 and ERK2 cascade • positive regulation of protein serine/threonine kinase activity Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	10253	24064
Ensembl	ENSG00000136158	ENSMUSG00000022114
UniProt	O43597	Q9QXV8
RefSeq (mRNA)	NM_005842	NM_011897
RefSeq (protein)	NP_005833	NP_036027
Location (UCSC)	Chr 13: 80.34 – 80.34 Mb	Chr 14: 105.89 – 105.9 Mb
PubMed search

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 (RTK's) including receptors for fibroblast growth factor (FGF),^[1] 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

References

1. Hacohen N, Kramer S, Sutherland D, Hiromi Y, Krasnow MA (January 1998). "sprouty encodes a novel antagonist of FGF signaling that patterns apical branching of the Drosophila airways". Cell 92 (2): 253–263. doi:10.1016/S0092-8674(00)80919-8. PMID 9458049.
2. "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): 2478–2487. doi:10.1182/blood-2008-05-156943. PMC 2656273. PMID 19147787.
4. Lee CC, Putnam AJ, Miranti CK, Gustafson M, Wang LM, Vande Woude GF, Gao CF (2004). "Overexpression of sprouty 2 inhibits HGF/SF-mediated cell growth, invasion, migration, and cytokinesis". Oncogene 23 (30): 5193–5202. doi:10.1038/sj.onc.1207646. PMID 15122328.
5. Sánchez A, Setién F, Martinez N, Oliva JL, Herranz M, Fraga MF, Alaminos M, Esteller M, Rojas JM. (2008). "Epigenetic inactivation of the ERK inhibitor Spry2 in B-cell diffuse lymphomas". Oncogene 27 (36): 4969–4972. doi:10.1038/onc.2008.129. PMID 18427547.
6. Bundschu K, Walter U, Schuh K (December 2006). "The VASP-Spred-Sprouty domain puzzle". J. Biol. Chem. 281 (48): 36477–36481. doi:10.1074/jbc.R600023200. PMID 16987806.
7. Wong, E S; Lim J; Low B C; Chen Q; Guy G R (February 2001). "Evidence for direct interaction between Sprouty and Cbl". J. Biol. Chem. (United States) 276 (8): 5866–5875. doi:10.1074/jbc.M006945200. ISSN 0021-9258. PMID 11053437.
8. Wong, Esther Sook Miin; Fong Chee Wai; Lim Jormay; Yusoff Permeen; Low Boon Chuan; Langdon Wallace Y; Guy Graeme R (September 2002). "Sprouty2 attenuates epidermal growth factor receptor ubiquitylation and endocytosis, and consequently enhances Ras/ERK signalling". EMBO J. (England) 21 (18): 4796–4808. doi:10.1093/emboj/cdf493. ISSN 0261-4189. PMC 126289. PMID 12234920.
9. Ng, Cherlyn; Jackson Rebecca A; Buschdorf Jan P; Sun Qingxiang; Guy Graeme R; Sivaraman J (March 2008). "Structural basis for a novel intrapeptidyl H-bond and reverse binding of c-Cbl-TKB domain substrates". EMBO J. (England) 27 (5): 804–816. doi:10.1038/emboj.2008.18. PMC 2265755. PMID 18273061.

Further reading

• 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 (2): 253–263. doi:10.1016/S0092-8674(00)80919-8. PMID 9458049.
• 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 (42): 32837–32845. doi:10.1074/jbc.M002156200. PMID 10887178.
• Glienke J, Fenten G, Seemann M, et al. (2000). "Human SPRY2 inhibits FGF2 signalling by a secreted factor". Mech. Dev. 96 (1): 91–99. doi:10.1016/S0925-4773(00)00378-6. PMID 10940627.
• Wong ES, Lim J, Low BC, et al. (2001). "Evidence for direct interaction between Sprouty and Cbl". J. Biol. Chem. 276 (8): 5866–5875. doi:10.1074/jbc.M006945200. PMID 11053437.
• Hartley JL, Temple GF, Brasch MA (2001). "DNA cloning using in vitro site-specific recombination". Genome Res. 10 (11): 1788–1795. doi:10.1101/gr.143000. PMC 310948. PMID 11076863.
• Wiemann S, Weil B, Wellenreuther R, et al. (2001). "Toward a catalog of human genes and proteins: sequencing and analysis of 500 novel complete protein coding human cDNAs". Genome Res. 11 (3): 422–435. doi:10.1101/gr.GR1547R. PMC 311072. PMID 11230166.
• Yusoff P, Lao DH, Ong SH, et al. (2002). "Sprouty2 inhibits the Ras/MAP kinase pathway by inhibiting the activation of Raf". J. Biol. Chem. 277 (5): 3195–3201. doi:10.1074/jbc.M108368200. PMID 11698404.
• Egan JE, Hall AB, Yatsula BA, Bar-Sagi D (2002). "The bimodal regulation of epidermal growth factor signaling by human Sprouty proteins". Proc. Natl. Acad. Sci. U.S.A. 99 (9): 6041–6046. doi:10.1073/pnas.052090899. PMC 122898. PMID 11983899.
• 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 (18): 4796–4808. doi:10.1093/emboj/cdf493. PMC 126289. PMID 12234920.
• Lim J, Yusoff P, Wong ES, et al. (2002). "The cysteine-rich sprouty translocation domain targets mitogen-activated protein kinase inhibitory proteins to phosphatidylinositol 4,5-bisphosphate in plasma membranes". Mol. Cell. Biol. 22 (22): 7953–7966. doi:10.1128/MCB.22.22.7953-7966.2002. PMC 134720. PMID 12391162.
• Hanafusa H, Torii S, Yasunaga T, Nishida E (2004). "Sprouty1 and Sprouty2 provide a control mechanism for the Ras/MAPK signalling pathway". Nat. Cell Biol. 4 (11): 850–858. doi:10.1038/ncb867. PMID 12402043.
• Yigzaw Y, Poppleton HM, Sreejayan N, et al. (2003). "Protein-tyrosine phosphatase-1B (PTP1B) mediates the anti-migratory actions of Sprouty". J. Biol. Chem. 278 (1): 284–288. doi:10.1074/jbc.M210359200. PMID 12414790.
• Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–16903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
• Hall AB, Jura N, DaSilva J, et al. (2003). "hSpry2 is targeted to the ubiquitin-dependent proteasome pathway by c-Cbl". Curr. Biol. 13 (4): 308–314. doi:10.1016/S0960-9822(03)00086-1. PMID 12593796.
• Sasaki A, Taketomi T, Kato R, et al. (2003). "Mammalian Sprouty4 suppresses Ras-independent ERK activation by binding to Raf1". Nat. Cell Biol. 5 (5): 427–432. doi:10.1038/ncb978. PMID 12717443.
• 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 (35): 33456–33464. doi:10.1074/jbc.M301317200. PMID 12815057.
• 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 (22): 22992–22995. doi:10.1074/jbc.M312498200. PMID 15031289.
• Dunham A, Matthews LH, Burton J, et al. (2004). "The DNA sequence and analysis of human chromosome 13". Nature 428 (6982): 522–528. doi:10.1038/nature02379. PMC 2665288. PMID 15057823.
• 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 (30): 5193–5202. doi:10.1038/sj.onc.1207646. PMID 15122328.
• Chi L, Zhang S, Lin Y, et al. (2004). "Sprouty proteins regulate ureteric branching by coordinating reciprocal epithelial Wnt11, mesenchymal Gdnf and stromal Fgf7 signalling during kidney development". Development 131 (14): 3345–3356. doi:10.1242/dev.01200. PMID 15201220.

External links

• SPRY2 human gene location in the UCSC Genome Browser.
• SPRY2 human gene details in the UCSC Genome Browser.