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). The Drosophila tracheal system is a network of epithelial tubes that delivers oxygen throughout the body. It arises at
mid-embryogenesis from 20 clusters of ectodermal cells. Each cluster invaginates and forms an epithelial sac that gives
rise to one tracheal hemisegment. A key regulator of branching is called sprouty (spry).
Spry mutations in Drosophila cause excessive branching. The spry protein is an antagonist of fibroblast growth factor
(FGF) signaling that patterns apical branching of the Drosophila airways. Sprouty is cysteine-rich protein that defines a new family of putative signaling molecules that
may similarly function as FGF antagonists in vertebrate development. Regulator of epidermal growth factor signaling: Sprouty. Wong ES et al. Sprouty was first discovered through its downregulatory effect on fibroblast growth factor (FGF) receptor pathway during tracheal development. Sprouty expression is also induced by the epidermal growth factor receptor (EGFR) cascade in some tissues, including the follicle cells of the ovary, the wing, and eye imaginal disc, and acts to abolish mitogen-activated protein (MAP) kinase activated by EGFR signaling. Sprouty is an intracellular protein that translocates to membrane ruffles upon EGF stimulation by virtue of a translocatory domain within its highly conserved cysteine-rich C-terminal region. 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. Overexpressed hSpry2 induces a prolonged EGFR-mediated MAP kinase activation. hSpry2 acts to sequester c-Cbl molecules from activated EGFR and impedes EGFR ubiquitination and downregulation, thereby potentiating the amplitude and longevity of intracellular signals. The strategies described herein encompass various methods that have been used to measure the status of EGFR following ectopic expression of hSpry2.
NCBI Summary:
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. [provided by RefSeq, Jul 2008]
General function
Intracellular signaling cascade
Comment
Cellular localization
Cytoplasmic
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Ovarian function
Comment
Exosomal miR-27 negatively regulates ROS production and promotes granulosa cells apoptosis by targeting SPRY2 in OHSS. Liu K et al. (2021) Ovarian hyperstimulation syndrome (OHSS) is one of the most dangerous iatrogenic complications in controlled ovarian hyperstimulation (COH). The exact molecular mechanism that induces OHSS remains unclear. In recent years, accumulating evidence found that exosomal miRNAs participate in many diseases of reproductive system. However, the specific role of miRNAs, particularly the follicular fluid-derived exosomal miRNAs in OHSS remains controversial. To identify differentially expressed follicular fluid exosomal miRNAs from OHSS and non-OHSS patients, the analysis based on miRNA-sequence was conducted. The levels of 291 miRNAs were significantly differed in exosomes from OHSS patients compared with normal control, and exosomal miR-27 was one of the most significantly down-regulated miRNAs in the OHSS group. By using MiR-27 mimic, we found it could increase ROS stress and apoptosis by down-regulating the expression of p-ERK/Nrf2 pathway by negatively regulating SPRY2. These data demonstrate that exosomal miRNAs are differentially expressed in follicular fluid between patients with and without OHSS, and follicular fluid exosomal miR-27 may involve in the pathological process of OHSS development.//////////////////hCG-induced Sprouty2 mediates amphiregulin-stimulated COX-2/PGE2 up-regulation in human granulosa cells: a potential mechanism for the OHSS. Cheng JC et al. (2016) Sprouty2 (SPRY2) is an important intracellular regulator for epidermal growth factor receptor (EGFR)-mediated ERK1/2 signaling. In human granulosa cells, although SPRY2 is expressed, its regulation and function remains complete unknown and must be defined. Our previous study has shown that human chorionic gonadotropin (hCG)/luteinizing hormone (LH) up-regulates the expression levels of EGF-like growth factor, amphiregulin (AREG), which subsequently contributes to the hCG/LH-induced COX-2 expression and PGE2 production. The aim of the present study was to investigate the effect of hCG on SPRY2 expression and the role of hCG-induced SPRY2 in AREG-stimulated COX-2 expression and PGE2 production in human granulosa cells. Our results demonstrated that the expression of SPRY2 was up-regulated by hCG treatment. Using pharmacological inhibitors and siRNA knockdown, we showed that activation of ERK1/2 signaling was required for hCG-induced up-regulation of SPRY2 expression. Further, SPRY2 knockdown attenuated the AREG-induced COX-2 expression and PGE2 production by inhibiting AREG-activated ERK1/2 signaling. Interestingly, we showed that SPRY2 expression levels were significantly increased in granulosa cells of ovarian hyperstimulation syndrome (OHSS) patients. These results for the first time elucidate the physiological roles of SPRY2 in human granulosa cells and suggest that aberrant expression of SPRY2 may contribute to the pathogenesis of OHSS.//////////////////
Claude Robert et al used differential
display and suppressive subtractive hybridization to identify
granulosa cell messenger RNA associated with bovine oocyte developmental
competence.
The main objective of this study was to identify mRNA expressed in the granulosa cells
characterizing differentiated follicles bearing developmentally competent bovine oocytes.
Analytical comparisons were made on mRNA pools of granulosa cells using differential display
reverse transcription polymerase chain reaction (DDRT) analysis and suppressive subtractive
hybridization (SSH). With the SSH analysis, four clones specific to
the presence of an incompetent oocyte were sequenced and none were identified, whereas 49
clones specific to the presence of a competent oocyte were sequenced and 18 were identified.
Among these clones, early growth response 1, sprouty 2, cytochrome C oxidase, matrix
metalloproteinase inducer, matrix metalloproteinase, epiregulin, prostaglandin receptor, and
progesterone receptor were the most relevant to the ovarian physiology being examined.
Expression regulated by
LH, Growth Factors/ cytokines
Comment
Divergence of intracellular signaling pathways and early response genes of two closely related fibroblast growth factors, FGF8 and FGF18, in bovine ovarian granulosa cells. Jiang Z et al. Fibroblast growth factors (FGFs) modulate ovarian function, including FGF8 and FGF18. These FGFs activate the same receptors, although FGF18 is unusual in that it increases apoptosis in ovarian granulosa cells whereas the 'typical' response to FGF is increased proliferation. The objective of the present study was to determine which early response genes and pathways are activated by FGF8 and FGF18 in bovine granulosa cells. FGF8 increased abundance of mRNA encoding the FGF-responsive genes SPRY1, SPRY2, SPRY4, NR4A1 and NR4A3 whereas FGF18 did not. FGF8 increased but FGF18 decreased levels of mRNA encoding the growth arrest associated protein, GADD45B. FGF8 increased ERK1/2 phosphorylation but FGF18 did not. Microarray analysis identified EGR1, FOS, FOSL1, BAMBI, XIRP1 and PLK2 as other FGF8 immediate-early response genes, and FGF18 stimulated EGR1, FOSL1, BAMBI and PLK2, but not FOS or XIRP1. This study demonstrates that FGF8 and FGF18 signal through divergent pathways in ovarian granulosa cells, despite reportedly similar receptor activation patterns.
Differential actions of fibroblast growth factors on intracellular pathways and target gene expression in bovine ovarian granulosa cells. Jiang Z et al. Several fibroblast growth factors (FGFs) alter ovarian granulosa cell function, including FGF1, FGF4 and FGF10. These ligands exhibit different patterns of receptor activation, and their mechanisms of action on granulosa cells remain unknown. The objective of the present study was to identify the major pathways and target genes activated by FGF1, FGF4 and FGF10 in primary oestrogenic granulosa cells cultured under serum-free conditions. FGF1 and FGF4 increased levels of mRNA encoding Sprouty family members, SPRY2 and SPRY4, and the orphan nuclear receptors NR4A1 and NR4A3. Both FGF1 and FGF4 decreased levels of mRNA encoding SPRY3 and the pro-apoptotic factor BAX. FGF1 but not FGF4 stimulated expression of the cell cycle regulator, GADD45B. In contrast, FGF10 altered the expression of none of these genes. Western blot demonstrated that FGF4 activated ERK1/2 and Akt signalling rapidly and transiently, whereas FGF10 elicited a modest and delayed activation of ERK1/2. These data show that FGF1 and FGF4 activate typical FGF signalling pathways in granulosa cells, whereas FGF10 activates atypical pathways. Fibroblast Growth Factors and Epidermal Growth Factor Cooperate with Oocyte-Derived Members of the TGFbeta Superfamily to Regulate Spry2 mRNA Levels in Mouse Cumulus Cells. Sugiura K et al. Mouse oocytes produce members of the transforming growth factor beta (TGFbeta) superfamily, including bone morphogenetic protein 15 (BMP15) and growth differentiation factor 9 (GDF9), as well as fibroblast growth factors (FGFs). These growth factors cooperate to regulate cumulus cell function. To identify potential mechanisms involved in these interactions, the ability of fully-grown oocytes to regulate expression of BMP or FGF antagonists in cumulus cells was examined. Oocytes promoted cumulus cell expression of transcripts encoding antagonists to TGFbeta superfamily members, including Grem2, Htra1, Htra3, and Nog mRNAs. In contrast, oocytes suppressed cumulus cell expression of Spry2 mRNA, which encodes a regulator of receptor tyrosine kinase signals, such as FGF and epidermal growth factor (EGF) receptor signals. The regulation of Spry2 mRNA levels in cumulus cells was studied further as a model for analysis of potential mechanisms for cooperativity of FGF/EGF signaling with oocyte-derived members of the TGFbeta superfamily. Oocytes suppressed basal and FGF-stimulated Spry2 mRNA levels in cumulus cells but, in contrast, promoted EGF-stimulated levels. Furthermore, recombinant TGFbeta superfamily proteins, including BMP15 and GDF9, mimicked these effects of oocytes. Elevated expression of Spry2 mRNA in cumulus and mural granulosa cells correlated with human chorionic gonadotropin (hCG)-induced expression of mRNAs encoding EGF-like peptides. Therefore, oocyte-derived members of the TGFbeta superfamily suppress FGF-stimulated Spry2 mRNA levels before the luteinizing hormone (LH) surge but promote Spry2 mRNA levels stimulated by EGF receptor-mediated signals after the surge.
Fibroblast growth factor-2 regulation of sprouty and NR4A genes in bovine ovarian granulosa cells. Jiang Z et al. Fibroblast growth factors (FGFs) alter ovarian function, at least in part by inhibiting steroid hormone secretion and affecting survival of granulosa cells. The mechanism of action of FGFs in ovarian follicle cells is largely unknown; in the present study we identified the major pathways used by FGF2 in nonluteinizing granulosa cells cultured under serum-free conditions. FGF2 increased abundance of mRNA encoding SPRY1, 2 and 4, but not SPRY3. Common pathways employed by FGF2 in the regulation of SPRY1, 2 and 4, as demonstrated by immunoblot and inhibitor studies, included ERK1/2 and Akt signaling. In contrast, PKC activation was necessary for FGF2-stimulated expression of SPRY1 and 4, but not for SPRY2. Intracellular calcium flux is critical and sufficient for SPRY2 expression, but not for SPRY1 and 4. We also identified the orphan nuclear receptor NR4A1 as a potential early response gene in FGF2 signaling, whose expression, like that of SPRY2, is critically dependent on calcium signaling. Together, these data identify FGF2-target genes in follicular granulosa cells, and demonstrate alternative pathway use for the differential control of SPRY genes. J. Cell. Physiol. ? 2010 Wiley-Liss, Inc.
Ovarian localization
Cumulus, Granulosa, Luteal cells
Comment
Fibroblast growth factor-2 regulation of sprouty and NR4A genes in bovine ovarian granulosa cells. Jiang ZL et al. Fibroblast growth factors (FGFs) alter ovarian function, at least in part by inhibiting steroid hormone secretion and affecting survival of granulosa cells. The mechanism of action of FGFs in ovarian follicle cells is largely unknown; in the present study we identified the major pathways used by FGF2 in non-luteinizing granulosa cells cultured under serum-free conditions. FGF2 increased abundance of mRNA encoding SPRY1, 2, and 4, but not SPRY3. Common pathways employed by FGF2 in the regulation of SPRY1, 2, and 4, as demonstrated by immunoblot and inhibitor studies, included ERK1/2 and Akt signaling. In contrast, PKC activation was necessary for FGF2-stimulated expression of SPRY1 and 4, but not for SPRY2. Intracellular calcium flux is critical and sufficient for SPRY2 expression, but not for SPRY1 and 4. We also identified the orphan nuclear receptor NR4A1 as a potential early response gene in FGF2 signaling, whose expression, like that of SPRY2, is critically dependent on calcium signaling. Together, these data identify FGF2-target genes in follicular granulosa cells, and demonstrate alternative pathway use for the differential control of SPRY genes. J. Cell. Physiol. 226: 1820-1827, 2011. ? 2010 Wiley-Liss, Inc.
Expression and regulation of Sprouty-2 in the granulosa-lutein cells of the corpus luteum Hurwitz A,et al .
Growth factor signalling has important modulatory roles in the process of human follicular growth, oocyte maturation and corpus luteum (CL) formation. Recently, Sprouty-2, an inhibitor of receptor tyrosine kinase (RTK) signalling pathway was advocated as a marker of oocyte competence in the bovine ovary. We sought to study Sprouty-2 expression and regulation in the human ovary. RT-PCR was used to detect Sprouty-2 mRNA in human granulosa-lutein cells (GLC) collected from follicular aspiration of IVF patients. The effect of epidermal and fibroblast growth factors (EGF and FGF) on Sprouty-2 mRNA expression in GLC was studied using quantitative real-time PCR. Immunohistochemistry was performed on cultured GLC, human CL and stimulated rat ovary sections. Sprouty-2 mRNA was expressed in human GLC. EGF and basic FGF, but not FGF4 and FGF10, increased Sprouty-2 mRNA expression in GLC. The Sprouty protein was localized to GLC of early and late human CL but not to the theca cell layer. Immunostaining of developing rat CL confirmed the temporal and spatial expression of Sprouty in humans. The detection of Sprouty-2 mRNA and protein in human GLC may suggest a role for Sprouty-2 during the final stages of follicle maturation and CL formation.