Alternative titles; symbols
HGNC Approved Gene Symbol: SFRP2
Cytogenetic location: 4q31.3 Genomic coordinates (GRCh38): 4:153,780,591-153,789,083 (from NCBI)
Members of the 'frizzled' (FZ) transmembrane protein family (see 606143) are receptors for Wnt family members (see 164975), cysteine-rich glycosylated ligands implicated in a variety of cellular processes, including control of cell polarity and malignant transformation. The secreted frizzled-related proteins (SFRPs) appear to act as soluble modulators of Wnt signaling by competing with membrane-bound frizzled receptors for the binding of secreted Wnt ligands.
Melkonyan et al. (1997) isolated cDNAs encoding the related human proteins SARP1 (secreted apoptosis-related protein-1), SARP2 (SFRP1; 604156) and SARP3 (SFRP5; 604158). Each of these proteins contains a signal peptide followed by an N-terminal cysteine-rich region (CRD) homologous to the extracellular CRD of frizzled-like proteins. The partial human SARP1 cDNA encodes a polypeptide that is 95% identical to mouse Sarp1. When expressed in a breast adenocarcinoma cell line, mouse SARP1 and human SARP2 exhibited opposite effects on cell sensitivity to proapoptotic stimuli. Whereas cells with SARP1 had higher resistance, cells expressing SARP2 were sensitized to apoptosis induced by tumor necrosis factor (191160) and ceramide. Expression of SARP1 or SARP2 modified the intracellular levels of beta-catenin (116806), an indicator of Wnt-frizzled protein interaction and signal transduction, suggesting that SARPs interfere with the Wnt-frizzled signaling pathway. Northern blot analysis revealed that the SARP genes have distinct expression patterns. SARP1 is expressed as 2.2- and 1.3-kb transcripts in several human tissues, with the highest levels in colon and small intestine.
Rattner et al. (1997) also cloned SFRP2. Transfection of membrane-anchored derivatives of SFRP2 and SFRP3 (605083) into embryonic kidney cells led to cell-surface binding of the Drosophila wingless protein.
Chang et al. (1999) reported that SARP1, or SFRP2, is highly and preferentially expressed in bovine retina throughout the inner nuclear layer. Within the retina, SARP3, or SFRP5, is specifically expressed in the retinal pigment epithelium (RPE), suggesting that photoreceptors are bathed by 2 complementary gradients of SFRP signaling molecules/modulators. The authors speculated that these putative inverse gradients of SFRP2 and SFRP5 might be involved in determining the polarity of photoreceptors and perhaps other cells in the retina.
Kobayashi et al. (2009) found that mouse Sfrp2 enhanced the procollagenase activity of human BMP1 (112264) in vitro.
Since dermal fibroblasts can have profound impacts on melanoma progression, Kaur et al. (2016) examined whether age-related changes in dermal fibroblasts could drive melanoma metastasis and response to targeted therapy. They found that aged fibroblasts secrete a Wnt antagonist, SFRP2, which activates a multistep signaling cascade in melanoma cells that results in a decrease in beta-catenin (116806) and microphthalmia-associated transcription factor (MITF; 156845), and ultimately the loss of a key redox effector, APE1 (107748). Loss of APE1 attenuates the response of melanoma cells to DNA damage induced by reactive oxygen species, rendering the cells more resistant to targeted therapy (vemurafenib). Age-related increases in SFRP2 also augment both angiogenesis and metastasis of melanoma cells. Kaur et al. (2016) concluded that their data provided an integrated view of how fibroblasts in the aged microenvironment contribute to tumor progression.
By analysis of somatic cell hybrids, Melkonyan et al. (1997) mapped the SARP1 gene to human chromosome 4. Chang et al. (1999) refined the map position to 4q31.3 using radiation hybrid analysis. They noted that this region shows homology of synteny with the central region of mouse chromosome 3, which contains the mouse Sfrp2 gene.
Kobayashi et al. (2009) found that Sfrp2 was expressed in heart during the fibrotic phase of myocardial infarction in a mouse model. Compared with wildtype hearts, Sfrp2 -/- hearts showed reduced fibrosis and improved cardiac function following myocardial infarction. In culture, Sfrp2 -/- mouse embryonic fibroblasts and adult heart fibroblasts showed reduced procollagen processing and extracellular matrix deposition compared with cultured wildtype fibroblasts.
Chang, J. T., Esumi, N., Moore, K., Li, Y., Zhang, S., Chew, C., Goodman, B., Rattner, A., Moody, S., Stetten, G., Campochiaro, P. A., Zack, D. J. Cloning and characterization of a secreted frizzled-related protein that is expressed by the retinal pigment epithelium. Hum. Molec. Genet. 8: 575-583, 1999. [PubMed: 10072424] [Full Text: https://doi.org/10.1093/hmg/8.4.575]
Kaur, A., Webster, M. R., Marchbank, K., Behera, R., Ndoye, A., Kugel, C. H., III, Dang, V. M., Appleton, J., O'Connell, M. P., Cheng, P., Valiga, A. A., Morisette, R., and 34 others. sFRP2 in the aged microenvironment drives melanoma metastasis and therapy resistance. Nature 532: 250-254, 2016. [PubMed: 27042933] [Full Text: https://doi.org/10.1038/nature17392]
Kobayashi, K., Luo, M., Zhang, Y., Wilkes, D. C., Ge, G., Grieskamp, T., Yamada, C., Liu, T.-C., Huang, G., Basson, C. T., Kispert, A., Greenspan, D. S., Sato, T. N. Secreted Frizzled-related protein 2 is a procollagen C proteinase enhancer with a role in fibrosis associated with myocardial infarction. Nature Cell Biol. 11: 46-55, 2009. [PubMed: 19079247] [Full Text: https://doi.org/10.1038/ncb1811]
Melkonyan, H. S., Chang, W. C., Shapiro, J. P., Mahadevappa, M., Fitzpatrick, P. A., Kiefer, M. C., Tomei, L. D., Umansky, S. R. SARPs: a family of secreted apoptosis-related proteins. Proc. Nat. Acad. Sci. 94: 13636-13641, 1997. [PubMed: 9391078] [Full Text: https://doi.org/10.1073/pnas.94.25.13636]
Rattner, A., Hsieh, J.-C., Smallwood, P. M., Gilbert, D. J., Copeland, N. G., Jenkins, N. A., Nathans, J. A family of secreted proteins contains homology to the cysteine-rich ligand-binding domain of frizzled receptors. Proc. Nat. Acad. Sci. 94: 2859-2863, 1997. [PubMed: 9096311] [Full Text: https://doi.org/10.1073/pnas.94.7.2859]