Alternative titles; symbols
HGNC Approved Gene Symbol: SPRY2
Cytogenetic location: 13q31.1 Genomic coordinates (GRCh38): 13:80,335,976-80,341,126 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 13q31.1 | {?IgA nephropathy, susceptibility to, 3} | 616818 | Autosomal dominant | 3 |
Sprouty family proteins are evolutionarily conserved inhibitors of tyrosine kinase signaling (Taketomi et al., 2005).
Hacohen et al. (1998) found that the Drosophila sprouty gene encodes a novel cysteine-rich protein that defines a new family of putative signaling molecules that may similarly function as fibroblast growth factor antagonists in vertebrate development. See SPRY1 (602465). By amino acid homology searches of databases, Hacohen et al. (1998) identified and cloned 3 different human homologs, SPRY1, SPRY2, and SPRY3 (300531), of the Drosophila sprouty gene. A full-length sequence of the human SPRY2 gene was identified.
Using in situ hybridization, Kuracha et al. (2013) found that Spry1, Spry2, and Spry4 (607984) were expressed in eyelid precursor cells of mice during epithelial invagination and peridermal migration.
Ding et al. (2003) determined that the SPRY2 gene contains 2 exons and spans 5 kb. Exon 1 is untranslated, and exon 2 contains the remainder of the 5-prime UTR, the open reading frame, and the 3-prime UTR. The promoter region contains an initiator element around the transcription start site, but no TATA or CAAT boxes. Strong basal transcription activity was driven by the proximal 0.4 kb, and electrophoretic mobility shift assays identified several cis-acting elements, including AP2 (107580), CREB (123810), SP1 (189906), and ETS1 (164720).
By genomic sequence analysis, Ding et al. (2003) mapped the SPRY2 gene to chromosome 13.
Gross (2018) mapped the SPRY2 gene to chromosome 13q31.1 based on an alignment of the SPRY2 sequence (GenBank AF039843) with the genomic sequence (GRCh38).
Lim et al. (2000) found that SPRY2 expressed by COS-1 cells localized to the cytoplasm and colocalized with microtubule proteins. Upon EGF (131530) stimulation, SPRY2 translocated to membrane ruffles. Deletion analysis identified the translocation domain as a highly conserved 105-amino acid C-terminal sequence.
Gross et al. (2001) found endogenous Spry2 expression upregulated, and Spry1 expression downregulated, by Fgf (see 131220) and Pdgf (see PDGFB 190040) in mouse fibroblasts. Both Spry proteins reduced cell growth upon overexpression. Gross et al. (2001) demonstrated that Spry1 and Spry2 inhibited the transcriptional events mediated by growth factor signaling and the induction of c-fos (164810), a gene required for DNA synthesis and cell division. Conditional overexpression of Spry1 and Spry2 in mouse fibroblasts specifically inhibited the Ras (HRAS; 190020)/Raf (164760)/Mapk (see 176948) pathway by preventing Ras activation. Spry1 and Spry2 did not interfere with the binding of Ras to Raf1, affect the PI3K (see 171833) pathway, or prevent the formation of Snt (607743)/Grb2 (108355)/Sos (see 182530) complexes. Gross et al. (2001) concluded that SPRY1 and SPRY2 act downstream of the GRB2-SOS complex to selectively uncouple growth factor signals from Ras activation and the MAPK pathway.
Egan et al. (2002) found that full-length SPRY1 and SPRY2, ectopically expressed in HeLa cells, potentiated EGF-induced MAPK1 activation. Truncation mutants containing only the C-terminal cysteine-rich domain inhibited MAPK1 activation. Further analysis of the N-terminal activation domain of SPRY2 indicated that potentiation resulted from the sequestration of CBL (165360), which downregulates receptor tyrosine kinases by targeting activated receptors for ubiquitination and degradation.
Through studies on Xenopus Spry1 and mouse Spry2, Hanafusa et al. (2002) determined that the inhibitory activity of the Spry proteins requires phosphorylation of a conserved tyrosine. Phosphorylated Spry proteins bound to the adaptor protein Grb2 and inhibited the recruitment of the Grb2-Sos complex to Frs2 or to Shp2 (176876).
Yusoff et al. (2002) presented evidence that SPRY2 exerts its inhibitory effect through RAF.
Lim et al. (2002) found that microinjection of active Rac (602048) into SPRY2-transfected mouse fibroblasts induced SPRY2 translocation through the C-terminal cysteine-rich translocation domain, placing SPRY2 downstream of Rac activation. The authors showed that the plasma membrane localization of SPRY2 is due to direct phosphatidylinositol 4,5-bisphosphate binding at the translocation domain, and that this interaction is essential for the inhibition of Ras/MAPK signaling by SPRY2.
Unlike humans, who have a continuous row of teeth, mice have only molars and incisors separated by a toothless region called a diastema. Klein et al. (2006) showed that Spry2 in epithelium and Spry4 in mesenchyme prevent diastema tooth formation by preventing diastema tooth buds from engaging in the Fgf-mediated bidirectional signaling that normally sustains tooth development.
During early lung development, airway tubes change shape. Tube length increases more than circumference as a large proportion of lung epithelial cells divide parallel to the airway longitudinal axis. Tang et al. (2011) showed that this bias is lost in mutants with increased extracellular signal-regulated kinase-1 (ERK1; 601795) and ERK2 (176948) activity, revealing a link between the ERK1/2 signaling pathway and the control of mitotic spindle orientation. Using a mathematical model, Tang et al. (2011) demonstrated that change in airway shape can occur as a function of spindle angle distribution determined by ERK1/2 signaling, independent of effects on cell proliferation or cell size and shape. Tang et al. (2011) identified sprouty genes (SPRY1, 602465; SPRY2), which encode negative regulators of fibroblast growth factor-10 (FGF10; 602115)-mediated RAS-regulated ERK1/2 signaling, as essential for controlling airway shape change during development through an effect on mitotic spindle orientation.
In affected members of a large Sicilian family with IgA nephropathy-3 (IGAN3; 616818), Milillo et al. (2015) identified a heterozygous missense mutation in the SPRY2 gene (R119W; 602466.0001). The mutation, which was found by exome sequencing, segregated with the disorder in family members over the age of 20 years; 3 family members under the age of 20 years did not have disease, although they were found to carry the mutation, suggesting age-dependent penetrance. Mutations in the SPRY2 gene were not found in 70 additional cases of apparently sporadic IgA nephropathy.
Shim et al. (2005) found that Spry2-null mice were born at expected mendelian ratios. By weaning, almost half of them died, and many of the surviving mice were smaller than normal. Analysis of vital organs indicated that abnormal gastrointestinal tract function caused the lethality. Spry2-null mice were also hearing impaired. While the middle ear ossicles, inner ear labyrinth, and spiral ganglion appeared normal, Spry2-null mice showed perturbations in the organ of Corti. Shim et al. (2005) determined that the defect was due to the postnatal transformation of a Deiters cell into a pillar cell. The cell fate change and hearing loss were partially rescued by reducing Fgf8 (600483) gene dosage. Shim et al. (2005) concluded that antagonism of FGF signaling by SPRY2 is essential for establishing the cytoarchitecture of the organ of Corti and for hearing.
Taketomi et al. (2005) found that Spry2-null mice developed enteric nerve hyperplasia, which led to esophageal achalasia and intestinal pseudoobstruction as evidenced by barium sulfate imaging. Glial cell line-derived neurotrophic factor (GDNF; 600837) induced hyperactivation of MAPK and Akt (164730) in enteric nerve cells, and anti-GDNF antibody administration corrected nerve hyperplasia. The findings suggested that Spry2 is a negative regulator of GDNF for the neonatal development or survival of enteric nerve cells.
In an elegant series of experiments, Metzger et al. (2008) presented the complete 3-dimensional branching pattern of lineage of the mouse bronchial tree, reconstructed from analysis of hundreds of developmental intermediates. Branching process is remarkably stereotyped and elegant: the tree is generated by 3 geometrically simple local modes of branching used in 3 different orders throughout the lung. Metzger et al. (2008) proposed that each mode of branching is controlled by genetically encoded subroutines, a series of local patterning and morphogenesis operations, which are themselves controlled by a more global master routine. They showed that this hierarchical and modular program is genetically tractable, and it is ideally suited to encoding and evolving the complex networks of the lung and other branched organs. The hierarchy is domain branching to build scaffolds, followed by planar bifurcation to make edges, and then orthogonal bifurcation, which makes surfaces and the interior. They found that in inversus viscerum mutants in the Dnahc11 (603339) gene, left-right axis specification was randomized and in about half the animals the positions and gross structures of organs were reversed. Lung-branching pattern and lineage was completely reversed in some embryos, demonstrating that deployment and coupling of the branching modes is under global genetic control and that it is downstream of Dnhc11 and the left-right asymmetry pathway. In contrast to this global effect, they found that Spry2-null mutations had local and subtle effects on branch pattern and lineage. The extra branches sprouted earlier and more proximally than the normal branches in these domains, expanding the domains towards the base of the parent branch. The ectopic branches formed additional generations, creating ectopic lineages indistinguishable from those of normal branches in the domain. Metzger et al. (2008) concluded that Spry2 restricts the number of branches in the 2 ventral domains, and in its absence normally nonbranching regions along the parent acquire the branching identity of more distal regions.
Kuracha et al. (2013) found that mice with conditional deletion of Spry1 and Spry2 in ocular surface epithelial cells were born with open eyelids due to failure of eyelid closure. Spry1 and Spry2 functioned redundantly to regulate eyelid closure. Spry deletion increased proliferation of eyelid epithelial cells and resulted in conjunctival hyperplasia with increased expression of cyclin D1 (CCND1; 168461) and cyclin D2 (CCND2; 123833). Further analyses demonstrated that the Spry deletion also led to induction of Fgf signaling targets in conjunctival epithelial cells; decreased phosphorylation of Jun (165160) in peridermal cells and increased phosphorylation of ERKs in conjunctival epithelial cells; reduced Shh (600725) expression in anterior eyelids with loss of clustering of Bmp4 (112262)-positive mesenchymal cells; reduced expression of Foxc1 (601090) and Foxc2 (602402); decreased expression of the Wnt signaling target Axin2 (604025) and increased expression of the Wnt antagonist SFRP (see 604156) in conjunctival epithelial cells; and decreased motility, reduced actin stress fibers, and reduced F-actin polymerization in peridermal cells.
In affected members of a large Sicilian family with autosomal dominant IgA nephropathy-3 (IGAN3; 616818), Milillo et al. (2015) identified a heterozygous c.355C-T transition (c.355C-T, NM_005842.2) in the SPRY2 gene, resulting in an arg119-to-trp (R119W) substitution at a highly conserved residue in the N-terminal region close to ser121, which is phosphorylated. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the dbSNP (build 132), 1000 Genomes Project, or Exome Sequencing Project databases, or in 52 Sicilian controls. It was identified in 3 unaffected family members who were under the age of 20 years, but not in any unaffected family members older than 20 years, consistent with segregation. Patient lymphoblastoid cells showed decreased amounts of SPRY2 mRNA, but normal protein levels resulting from increased stability of the mutant protein; there was no difference in the ratio between phosphorylated and nonphosphorylated forms compared to controls. Patient cells showed downregulation of the MAPK/ERK1/2 pathway. Cells from 2 unrelated patients with IgA nephropathy who did not have SPRY2 mutations also showed downregulation of the MAPK/ERK1/2 pathway, suggesting that it may be a common disease mechanism.
Ding, W., Bellusci, S., Shi, W., Warburton, D. Functional analysis of the human Sprouty2 gene promoter. Gene 322: 175-185, 2003. [PubMed: 14644509] [Full Text: https://doi.org/10.1016/j.gene.2003.09.004]
Egan, J. E., Hall, A. B., Yatsula, B. A., Bar-Sagi, D. The bimodal regulation of epidermal growth factor signaling by human Sprouty proteins. Proc. Nat. Acad. Sci. 99: 6041-6046, 2002. [PubMed: 11983899] [Full Text: https://doi.org/10.1073/pnas.052090899]
Gross, I., Bassit, B., Benezra, M., Licht, J. D. Mammalian Sprouty proteins inhibit cell growth and differentiation by preventing Ras activation. J. Biol. Chem. 276: 46460-46468, 2001. [PubMed: 11585837] [Full Text: https://doi.org/10.1074/jbc.M108234200]
Gross, M. B. Personal Communication. Baltimore, Md. 6/7/2018.
Hacohen, N., Kramer, S., Sutherland, D., Hiromi, Y., Krasnow, M. A. Sprouty encodes a novel antagonist of FGF signaling that patterns apical branching of the Drosophila airways. Cell 92: 253-263, 1998. [PubMed: 9458049] [Full Text: https://doi.org/10.1016/s0092-8674(00)80919-8]
Hanafusa, H., Torii, S., Yasunaga, T., Nishida, E. Sprouty1 and Sprouty2 provide a control mechanism for the Ras/MAPK signalling pathway. Nature Cell Biol. 4: 850-858, 2002. [PubMed: 12402043] [Full Text: https://doi.org/10.1038/ncb867]
Klein, O. D., Minowada, G., Peterkova, R., Kangas, A., Yu, B. D., Lesot, H., Peterka, M., Jernvall, J., Martin, G. R. Sprouty genes control diastema tooth development via bidirectional antagonism of epithelial-mesenchymal FGF signaling. Dev. Cell 11: 181-190, 2006. [PubMed: 16890158] [Full Text: https://doi.org/10.1016/j.devcel.2006.05.014]
Kuracha, M. R., Siefker, E., Licht, J. D., Govindarajan, V. Spry1 and Spry2 are necessary for eyelid closure. Dev. Biol. 383: 227-238, 2013. [PubMed: 24055172] [Full Text: https://doi.org/10.1016/j.ydbio.2013.09.014]
Lim, J., Wong, E. S. M., Ong, S. H., Yusoff, P., Low, B. C., Guy, G. R. 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, 2000. [PubMed: 10887178] [Full Text: https://doi.org/10.1074/jbc.M002156200]
Lim, J., Yusoff, P., Wong, E. S. M., Chandramouli, S., Lao, D.-H., Fong, C. W., Guy, G. R. The cysteine-rich Sprouty translocation domain targets mitogen-activated protein kinase inhibitory proteins to phosphatidylinositol 4,5-bisphosphate in plasma membranes. Molec. Cell. Biol. 22: 7953-7966, 2002. [PubMed: 12391162] [Full Text: https://doi.org/10.1128/MCB.22.22.7953-7966.2002]
Metzger, R. J., Klein, O. D., Martin, G. R., Krasnow, M. A. The branching programme of mouse lung development. Nature 453: 745-750, 2008. [PubMed: 18463632] [Full Text: https://doi.org/10.1038/nature07005]
Milillo, A., La Carpia, F., Costanzi, S., D'Urbano, V., Martini, M., Lanuti, P., Vischini, G., Larocca, L. M., Marchisio, M., Miscia, S., Amoroso, A., Gurrieri, F., Sangiorgi, E. A SPRY2 mutation leading to MAPK/ERK pathway inhibition is associated with an autosomal dominant form of IgA nephropathy. Europ. J. Hum. Genet. 23: 1673-1678, 2015. [PubMed: 25782674] [Full Text: https://doi.org/10.1038/ejhg.2015.52]
Shim, K., Minowada, G., Coling, D. E., Martin, G. R. Sprouty2, a mouse deafness gene, regulates cell fate decisions in the auditory sensory epithelium by antagonizing FGF signaling. Dev. Cell 8: 553-564, 2005. [PubMed: 15809037] [Full Text: https://doi.org/10.1016/j.devcel.2005.02.009]
Taketomi, T., Yoshiga, D., Taniguchi, K., Kobayashi, T., Nonami, A., Kato, R., Sasaki, M., Sasaki, A., Ishibashi, H., Moriyama, M., Nakamura, K., Nishimura, J., Yoshimura, A. Loss of mammalian Sprouty2 leads to enteric neuronal hyperplasia and esophageal achalasia. Nature Neurosci. 8: 855-857, 2005. [PubMed: 15937482] [Full Text: https://doi.org/10.1038/nn1485]
Tang, N., Marshall, W. F., McMahon, M., Metzger, R. J., Martin, G. R. Control of mitotic spindle angle by the RAS-regulated ERK1/2 pathway determines lung tube shape. Science 333: 342-345, 2011. [PubMed: 21764747] [Full Text: https://doi.org/10.1126/science.1204831]
Yusoff, P., Lao, D.-H., Ong, S. H., Wong, E. S. M., Lim, J., Lo, T. L., Leong, H. F., Fong, C. W., Guy, G. R. Sprouty2 inhibits the Ras/MAP kinase pathway by inhibiting the activation of Raf. J. Biol. Chem. 277: 3195-3201, 2002. [PubMed: 11698404] [Full Text: https://doi.org/10.1074/jbc.M108368200]