SPRY1 (Sprouty Homolog 1, Antagonist Of FGF Signaling (Drosophila))

2013-10-01   Behnam Nabet , Jonathan D Licht 

Feinberg School of Medicine, Northwestern University, Hematology\\\/Oncology Division, 303 East Chicago Avenue, Chicago, IL 60611-3008, USA

Identity

HGNC
LOCATION
4q28.1
LOCUSID
ALIAS
hSPRY1
FUSION GENES

DNA/RNA

Description

SPROUTY1 (SPRY1) is located on the plus strand of chromosome 4 (124319541-124324915) and contains three exons (Figure 1A). The third exon is the coding exon.

Transcription

Four transcript variants exist for SPRY1, all of which encode the same protein (according to UCSC genome browser (hg19)). Transcript variant 1 contains three exons, the last of which is the coding exon. Transcript variant 2 lacks exon 2 but retains the same coding exon as transcript variant 1. Transcript variants 3 and 4 also lack exon 2, have alternative promoters, and retain the same third coding exon (Figure 1B).

Proteins

Description

SPRY1 is a member of the SPRY gene family, which is composed of four genes (SPRY1, SPRY2, SPRY3, and SPRY4). SPRY1 protein is composed of 319 amino acids, which include a conserved serine-rich motif and a conserved cysteine-rich domain (Figure 1C). The C-terminal cysteine-rich domain of SPRY1 contains 23 cysteine residues, 19 of which are shared among the four family members (reviewed in Guy et al., 2009). This cysteine-rich domain facilitates homo- and heterodimer formation between SPRY proteins (Ozaki et al., 2005).
SPRY1 functions as a regulator of fundamental signaling pathways and its activity is regulated by post-translational modifications. Spry1 is phosphorylated in response to the growth factors, fibroblast growth factor (FGF) and platelet-derived growth factor (PDGF) (Mason et al., 2004). Xenopus xSpry1 is phosphorylated on the tyrosine 53 (Tyr53) residue in response to FGF treatment (Hanafusa et al., 2002). The xSpry1 Y53F mutant, which prevents this phosphorylation event, functions as a dominant-negative suggesting that phosphorylation is required for xSpry1 inhibitory activity toward growth signaling pathways (Hanafusa et al., 2002). Serine residues of Spry1 are also phosphorylated in response to FGF (Impagnatiello et al., 2001). Finally, Spry1 can be palmitoylated, and serves as a possible mechanism of membrane localization (Impagnatiello et al., 2001).
Atlas Image
Figure 1. SPROUTY1 (SPRY1) genomic context, transcript variants, and protein structure. (A) UCSC genome browser (hg19) snapshot of SPRY1 genomic context on chromosome 4q28.1. Image modified from: UCSC genome Bioinformatics. (B) UCSC genome browser (hg19) snapshot of the four SPRY1 transcripts. All transcripts retain the same coding exon. Image modified from: UCSC genome Bioinformatics. (C) Schematic of SPRY1 protein. Highlighted is the conserved N-terminal tyrosine 53 (Y53) that is phosphorylated in response to growth factor treatment, the serine-rich motif (SRM) that is phosphorylated upon growth factor treatment, and the conserved C-terminal cysteine-rich domain (CRD).

Expression

Spry1 is expressed in localized domains throughout organogenesis in the developing mouse embryo and in adult tissues (Minowada et al., 1999). Spry1 is expressed during the development of the brain, salivary gland, lung, digestive tract, lens, and kidney (Minowada et al., 1999, Zhang et al., 2001, Boros et al., 2006). Notably, Spry1 is expressed in the developing mouse kidney at the condensing mesenchyme and the ureteric tree (Gross et al., 2003). During mouse embryonic development Spry1 expression patterns strongly correlate with regions of FGF expression, which may directly promote Spry1 gene activation (Minowada et al., 1999). For example, Spry1 expression is induced in response to FGF8 in explant cultures of the mouse mandibular arch (Minowada et al., 1999).
Spry1 expression is dynamically regulated in response to environmental stimuli, although the kinetics of activation vary depending on the specific cell line or stimulus used. Serum starved NIH-3T3 cells treated with FGF, PDGF, epidermal growth factor (EGF) or phorbol 12-myristate-13-acetate (PMA), upregulate Spry1 mRNA expression 30-60 minutes after stimulation (Ozaki et al., 2001). However, at time-points beyond 2 hours, Spry1 mRNA expression is downregulated in serum-starved NIH-3T3 cells treated with FGF (Gross et al., 2001). Taken together these results may reflect a transient burst of Spry1 mRNA induction in response to growth factor signaling. In mouse microvascular endothelial cells (1G11), Spry1 mRNA expression is modulated as cells are serum deprived and stimulated with FGF. Spry1 expression increases upon serum starvation, decreases after 2 hours of FGF treatment, and then increases after 6-18 hours of FGF treatment (Impagnatiello et al., 2001). Spry1 mRNA expression is increased in Th1 cells upon activation of T-cell receptor (TCR) signaling pathways (Choi et al., 2006). SPRY1 protein expression increases in U937 cells upon interferon α or β treatment (Sharma et al., 2012). Finally, SPRY1 mRNA expression increases when human umbilical vein endothelial cells (HUVECs) are subject to hypoxic conditions (Lee et al., 2010).
Spry1 activity is also regulated by transcription factors such as Wilms Tumor 1 (WT1), which binds directly to the Spry1 promoter to activate its expression (Gross et al., 2003). Furthermore, Spry1 expression is directly repressed by microRNA-21 (miR-21) (Thum et al., 2008). Importantly, miR-21 mediated repression of Spry1 leads to increased Ras-extracellular signal regulated kinase (Erk) signaling pathway activation causing cardiac fibrosis and dysfunction (Thum et al., 2008).

Localisation

SPRY1 is primarily expressed in the cytoplasm and its localization to the plasma membrane is modulated upon serum deprivation and growth factor treatment. Impagnatiellio et al. demonstrated that in freely growing HUVECs, SPRY1 is localized to perinuclear and vesicular structures as well as the plasma membrane. Upon serum deprivation, SPRY1 remains cytoplasmic but is no longer detected at the plasma membrane. In response to FGF treatment, SPRY1 is again localized to the plasma membrane (Impagnatiello et al., 2001). Similarly, ectopic Spry1 in COS-1 cells translocates to membrane ruffles upon EGF treatment (Lim et al., 2002).

Function

Elegant studies in Drosophila identified dSpry as a novel inhibitor of FGF and EGF signaling pathway activation during tracheal branching, oogenesis, and eye development, with specificity towards regulating the Ras-Erk cascade (Hacohen et al., 1998; Casci et al., 1999; Kramer et al., 1999; Reich et al., 1999). Similarly, subsequent studies using mammalian cell lines and mouse models revealed that SPRY1 negatively regulates receptor tyrosine kinase (RTK) signaling pathway activation in various cellular contexts. As a result, SPRY1 controls organ development and fundamental biologic processes including cell proliferation, differentiation, survival, and angiogenesis (reviewed in Mason et al., 2006; Edwin et al., 2009).
In vivo loss-of-function experiments in mice demonstrated that Spry1 is a key regulator of proper organ and tissue development. Spry1 knockout (Spry1-/-) mice have striking defects in branching morphogenesis of the kidney, develop kidney epithelial cysts, and a disease resembling the human condition known as congenital anomalies of the kidney and urinary track (Basson et al., 2005; Basson et al., 2006). Conditional deletion of Spry1 in satellite cells demonstrated that Spry1 is required for the muscle stem cell quiescence during muscle cell regeneration as well as the maintenance of muscle stem cell quiescence during ageing (Shea et al., 2010; Chakkalakal et al., 2012). Studies conditionally deleting both Spry1 and Spry2 revealed that Spry1 and Spry2 are also critical regulators of proper lens and cornea, as well as brain development. The conditional deletion of the combination of Spry1 and Spry2 results in lens and cornea defects, and cataract formation (Kuracha et al., 2011; Shin et al., 2012). Spry1 and Spry2 conditional double knockout mutants lack proper patterning of the murine brain, and altered gene expression downstream of Fgf signaling pathway activation (Faedo et al., 2010).
SPRY family members including SPRY1 function as inhibitors of Ras-Erk signaling, although the point at which SPRY inhibits pathway activation remains controversial (reviewed in Mason et al., 2006). In the developing mouse kidney, Spry1 antagonizes the glial cell line-derived neurotrophic factor (GDNF)/Ret signaling pathway to control Erk activation (Basson et al., 2005). Similarly, conditional deletion of the combination of Spry1 and Spry2 in the murine lens leads to elevated Erk activation, as well as activation of downstream FGF target genes (Kuracha et al., 2011; Shin et al., 2012). In cell lines, Spry1 regulates signaling pathway activation in response to various defined stimuli. Spry1 inhibits Ras-Erk pathway activation in response to growth factors including FGF, PDGF, and VEGF, correlating with the ability of Spry1 to control cell proliferation and differentiation (Gross et al., 2001; Impagnatiello et al., 2001). By contrast, overexpression of SPRY1 in HeLa cells leads to increased Ras-Erk pathway activation in response to EGF (Egan et al., 2002). Recent evidence demonstrates that SPRY1 is involved in inhibiting ERK and p38 MAPK activation in response to interferons, limiting expression of interferon-stimulated genes and decreasing interferon-mediated biologic responses (Sharma et al., 2012).
Growing evidence also links the SPRY family as critical regulators of phosphoinositide 3-kinase (PI3K)-protein kinase B (PKB, also known as AKT) and phospholipase C gamma (PLCγ)- protein kinase C (PKC) pathway activation. In an inner medullary collecting duct cell line, Spry1 knockdown results in enhanced and prolonged phosphorylated, activated Akt in response to GDNF treatment (Basson et al., 2006). Spry1 binds to PLCγ and inhibits PLCγ pathway activation, resulting in decreased inositol triphosphate (IP3), calcium, and diacylglycerol (DAG) production (Akbulut et al., 2010).
SPRY1 regulates TCR signaling pathway activation in a cell-type specific manner. In Th1 cells (Choi et al., 2006) and CD4+ cells (Collins et al., 2012), Spry1 inhibits signaling pathway activation, while in naïve T-cells Spry1 potentiates signaling pathway activation (Choi et al., 2006). Spry1 binds to numerous signaling intermediates including linker of activated T-cells (LAT), PLCγ1, and c-Cbl to suppress Ras-Erk, nuclear factor of activated T-cells (NFAT) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) pathway activation (Lee et al., 2009).

Implicated in

Entity name
Breast cancer
Note
SPRY1 is significantly downregulated in the majority of breast cancer cases. This down-regulation was observed by comparing the expression of SPRY1 in breast cancer tumors and matched normal tissues using cDNA arrays (39/50 (78%) of paired samples) and quantitative real-time PCR (qRT-PCR) (18/19 (94%) of paired samples) (Lo et al., 2006). This data suggests that SPRY1 has tumor suppressive activity in breast cancer.
Entity name
Clear cell renal cell carcinoma (ccRCC)
Note
Gene expression profiling of 29 ccRCC patient tumors revealed that SPRY1 expression serves as a prognostic biomarker associated with good outcome (Takahashi et al., 2001).
Entity name
Embryonal rhabdomyosarcoma subtype (ERMS)
Note
cDNA microarray and Affymetrix microarray experiments revealed that SPRY1 mRNA expression is elevated in ERMS tumors compared to alveolar rhabdomyosarcoma subtype (RMS) tumors. Oncogenic Ras mutations leading to elevated Ras-Erk pathway activation in ERMS cell lines, result in increased SPRY1 protein expression. Inhibition of SPRY1 in ERMS cell lines decreases cell growth, survival and xenograft formation (Schaaf et al., 2010). This data suggests that in ERMS tumors driven by oncogenic Ras with elevated SPRY1 expression, targeting SPRY1 may prove to be efficacious.
Entity name
Glioma
Note
Analysis of a glioma dataset containing expression data from 276 tumor samples revealed that SPROUTY (SPRY1, SPRY2, and SPRY4) genes are coordinately upregulated in EGFR amplified gliomas (Ivliev et al., 2010). The role and significance of SPRY1 in glioma has not been functionally addressed.
Entity name
Hepatocellular carcinoma
Note
An initial study comparing hepatocellular carcinoma tumors with non-tumor livers, found that SPRY2 was significantly downregulated, while SPRY1 was not significantly downregulated in tumor tissue (Fong et al., 2006). qRT-PCR analysis of tissues from hepatocellular carcinoma patients revealed that SPRY1 expression levels are upregulated in 68% of patients, while SPRY2 and SPRY4 are commonly downregulated (79% and 75%, respectively). The upregulated SPRY1 levels were found in patients that did not display cirrhosis in their non-tumor tissue (Sirivatanauksorn et al., 2012). Recent evidence suggests that downregulation of SPRY1 in liver cancers occurs through miR-21 mediated repression (Jin et al., 2013).
Entity name
Medullary thyroid carcinoma (MTC)
Note
SPRY1 has been proposed to have tumor suppressive activity in MTC. Spry1-/- mice display evidence of thyroid cell hyperplasia. Overexpression of Spry1 in an MTC cell line with low Spry1 expression reduces cell proliferation and tumor formation in xenografts through activation of the CDKN2A locus. The majority of human MTC samples tested display promoter methylation and downregulation of SPRY1 expression, in line with the proposed tumor suppressive role of SPRY1 in MTC (Macia et al., 2012).
Entity name
Non-small cell lung cancer (NSCLC)
Note
SPRY1 mRNA expression is upregulated in NSCLC tumors compared to matched normal lung tissues, while SPRY2 mRNA expression is commonly downregulated (Sutterluty et al., 2007).
Entity name
Ovarian cancer
Note
SPRY1 mRNA and protein expression varies in ovarian cancer cell lines. 4/7 cell lines (SKOV-3, CAOV-3, OV-90, and IGROV-1) display significantly lower SPRY1 protein expression, 1/7 cell lines (OVCAR-3) display significantly higher SPRY1 protein expression, and 2/7 cell lines (1A9 and A2780) display equivalent SPRY1 expression, as compared to normal primary human ovarian cells (Moghaddam et al., 2012).
Entity name
Prostate cancer
Note
SPRY1 expression is downregulated in prostate cancer. This downregulation was observed by comparing prostate cancer tissue to normal tissues using immunohistochemistry (40% of 407 of paired samples) and qRT-PCR (16/20 of samples assessed) (Kwabi-Addo et al., 2004). Moderate down-regulation of SPRY1 mRNA expression was also detected in an independent study (Fritzsche et al., 2006). In addition, SPRY1 protein levels are significantly decreased in prostate cancer cell lines (LNCaP, Du145, and PC-3) compared to prostatic epithelial cell lines. Overexpression of SPRY1 in LNCaP and PC-3 cells significantly inhibits cell growth (Kwabi-Addo et al., 2004). Increased methylation of the SPRY1 promoter and miR-21 mediated repression are in part responsible for abnormal SPRY1 silencing that occurs in prostate cancer (Kwabi-Addo et al., 2009; Darimipourain et al., 2011). More recently, it was confirmed in vivo that Spry1 and Spry2 function together to inhibit prostate cancer progression (Schutzman and Martin, 2012). The conditional deletion of both Spry1 and Spry2 in mouse prostate epithelium results in ductal hyperplasia and low-grade prostatic intraepithelial neoplasia. Notably, the deletion of Spry1 and Spry2 synergizes with reduction of Pten to increase the grade and invasiveness of prostate tumorigenesis through increased PI3K-Akt and Ras-Erk signaling pathway activation (Schutzman and Martin, 2012).

Bibliography

Pubmed IDLast YearTitleAuthors
207199622010Sprouty proteins inhibit receptor-mediated activation of phosphatidylinositol-specific phospholipase C.Akbulut S et al
156917642005Sprouty1 is a critical regulator of GDNF/RET-mediated kidney induction.Basson MA et al
170229622006Branching morphogenesis of the ureteric epithelium during kidney development is coordinated by the opposing functions of GDNF and Sprouty1.Basson MA et al
171415392006Sef and Sprouty expression in the developing ocular lens: implications for regulating lens cell proliferation and differentiation.Boros J et al
100898811999Sprouty, an intracellular inhibitor of Ras signaling.Casci T et al
230231262012The aged niche disrupts muscle stem cell quiescence.Chakkalakal JV et al
166703122006Dual effects of Sprouty1 on TCR signaling depending on the differentiation state of the T cell.Choi H et al
231667732012Regulation of CD4⁺ and CD8⁺ effector responses by Sprouty-1.Collins S et al
218260972011Transcriptional and post-transcriptional regulation of Sprouty1, a receptor tyrosine kinase inhibitor in prostate cancer.Darimipourain M et al
195709492009Intermolecular interactions of Sprouty proteins and their implications in development and disease.Edwin F et al
119838992002The bimodal regulation of epidermal growth factor signaling by human Sprouty proteins.Egan JE et al
202372722010Repression of Fgf signaling by sprouty1-2 regulates cortical patterning in two distinct regions and times.Faedo A et al
164890042006Sprouty 2, an inhibitor of mitogen-activated protein kinase signaling, is down-regulated in hepatocellular carcinoma.Fong CW et al
169544332006Concomitant down-regulation of SPRY1 and SPRY2 in prostate carcinoma.Fritzsche S et al
115858372001Mammalian sprouty proteins inhibit cell growth and differentiation by preventing ras activation.Gross I et al
128829702003The receptor tyrosine kinase regulator Sprouty1 is a target of the tumor suppressor WT1 and important for kidney development.Gross I et al
194236412009Sprouty proteins: modified modulators, matchmakers or missing links?Guy GR et al
94580491998sprouty encodes a novel antagonist of FGF signaling that patterns apical branching of the Drosophila airways.Hacohen N et al
124020432002Sprouty1 and Sprouty2 provide a control mechanism for the Ras/MAPK signalling pathway.Hanafusa H et al
112384632001Mammalian sprouty-1 and -2 are membrane-anchored phosphoprotein inhibitors of growth factor signaling in endothelial cells.Impagnatiello MA et al
211596302010Coexpression network analysis identifies transcriptional modules related to proastrocytic differentiation and sprouty signaling in glioma.Ivliev AE et al
233554542013microRNA 21-mediated suppression of Sprouty1 by Pokemon affects liver cancer cell growth and proliferation.Jin XL et al
102260101999Sprouty: a common antagonist of FGF and EGF signaling pathways in Drosophila.Kramer S et al
217430072011Spry1 and Spry2 are necessary for lens vesicle separation and corneal differentiation.Kuracha MR et al
191648982009DNA methylation and aberrant expression of Sprouty1 in human prostate cancer.Kwabi-Addo B et al
199150612009Recruitment of Sprouty1 to immune synapse regulates T cell receptor signaling.Lee JS et al
200546162010Sprouty1 inhibits angiogenesis in association with up-regulation of p21 and p27.Lee S et al
123911622002The cysteine-rich sprouty translocation domain targets mitogen-activated protein kinase inhibitory proteins to phosphatidylinositol 4,5-bisphosphate in plasma membranes.Lim J et al
164694332006Sprouty and cancer: the first terms report.Lo TL et al
221580372012Sprouty1 is a candidate tumor-suppressor gene in medullary thyroid carcinoma.Macià A et al
163377952006Sprouty proteins: multifaceted negative-feedback regulators of receptor tyrosine kinase signaling.Mason JM et al
104986821999Vertebrate Sprouty genes are induced by FGF signaling and can cause chondrodysplasia when overexpressed.Minowada G et al
232511572012Initial report on differential expression of sprouty proteins 1 and 2 in human epithelial ovarian cancer cell lines.Moghaddam SM et al
114787642001ERK pathway positively regulates the expression of Sprouty genes.Ozaki K et al
163399692005Efficient suppression of FGF-2-induced ERK activation by the cooperative interaction among mammalian Sprouty isoforms.Ozaki K et al
104570221999Sprouty is a general inhibitor of receptor tyrosine kinase signaling.Reich A et al
200681622010Silencing of SPRY1 triggers complete regression of rhabdomyosarcoma tumors carrying a mutated RAS gene.Schaaf G et al
231505962012Sprouty genes function in suppression of prostate tumorigenesis.Schutzman JL et al
230742222012Sprouty proteins are negative regulators of interferon (IFN) signaling and IFN-inducible biological responses.Sharma B et al
201447852010Sprouty1 regulates reversible quiescence of a self-renewing adult muscle stem cell pool during regeneration.Shea KL et al
225173122012Sprouty is a negative regulator of transforming growth factor β-induced epithelial-to-mesenchymal transition and cataract.Shin EH et al
219324112012Differential expression of sprouty genes in hepatocellular carcinoma.Sirivatanauksorn Y et al
175103162007Down-regulation of Sprouty2 in non-small cell lung cancer contributes to tumor malignancy via extracellular signal-regulated kinase pathway-dependent and -independent mechanisms.Sutterlüty H et al
114936962001Gene expression profiling of clear cell renal cell carcinoma: gene identification and prognostic classification.Takahashi M et al
190434052008MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts.Thum T et al
117312512001Expression of Sprouty genes 1, 2 and 4 during mouse organogenesis.Zhang S et al

Other Information

Locus ID:

NCBI: 10252
MIM: 602465
HGNC: 11269
Ensembl: ENSG00000164056

Variants:

dbSNP: 10252
ClinVar: 10252
TCGA: ENSG00000164056
COSMIC: SPRY1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000164056ENST00000339241O43609
ENSG00000164056ENST00000394339O43609
ENSG00000164056ENST00000505319D6REX7
ENSG00000164056ENST00000507703D6RHD2
ENSG00000164056ENST00000508849D6RIE6
ENSG00000164056ENST00000610581O43609
ENSG00000164056ENST00000622283O43609
ENSG00000164056ENST00000651917O43609

Expression (GTEx)

0
50
100
150
200
250

Pathways

PathwaySourceExternal ID
Signal TransductionREACTOMER-HSA-162582
Signaling by EGFRREACTOMER-HSA-177929
EGFR downregulationREACTOMER-HSA-182971

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
119838992002The bimodal regulation of epidermal growth factor signaling by human Sprouty proteins.44
169544332006Concomitant down-regulation of SPRY1 and SPRY2 in prostate carcinoma.30
206286242010Evaluation of candidate stromal epithelial cross-talk genes identifies association between risk of serous ovarian cancer and TERT, a cancer susceptibility "hot-spot".29
202372722010Repression of Fgf signaling by sprouty1-2 regulates cortical patterning in two distinct regions and times.28
265269942015Age-Associated Methylation Suppresses SPRY1, Leading to a Failure of Re-quiescence and Loss of the Reserve Stem Cell Pool in Elderly Muscle.27
200681622010Silencing of SPRY1 triggers complete regression of rhabdomyosarcoma tumors carrying a mutated RAS gene.25
234411722013miR-21 promotes fibrogenic epithelial-to-mesenchymal transition of epicardial mesothelial cells involving Programmed Cell Death 4 and Sprouty-1.25
159500612005Human placental Hofbauer cells express sprouty proteins: a possible modulating mechanism of villous branching.21
228800132012Stromal expression of decorin, Semaphorin6D, SPARC, Sprouty1 and Tsukushi in developing prostate and decreased levels of decorin in prostate cancer.19
230742222012Sprouty proteins are negative regulators of interferon (IFN) signaling and IFN-inducible biological responses.17

Citation

Behnam Nabet ; Jonathan D Licht

SPRY1 (Sprouty Homolog 1, Antagonist Of FGF Signaling (Drosophila))

Atlas Genet Cytogenet Oncol Haematol. 2013-10-01

Online version: http://atlasgeneticsoncology.org/gene/51064/spry1