SFRP4 (Secreted Frizzled-Related Protein 4)

2009-04-01   Kendra S Carmon , David S Loose 

University of Texas Health Science Center Houston, Houston, TX 77030, USA




Atlas Image
Diagram illustrates SFRP4 gene that contains a total of six exons.


The SFRP4 gene spans 10.99 kb on the short arm of chromosome 7 and is transcribed from the minus strand in the centromere-to-telomere orientation. The gene is encoded by six exons with the translation initiation codon in the first exon.


The SFRP4 mRNA transcript is 2974 bp, 1041 bp are coding sequence. Ensembl data predicts a second transcript from the SFRP4 gene, lacking the 81 bp exon 2, although this has not been demonstrated.


Atlas Image
Diagram illustrates the full length SFRP4 protein which contains a signal peptide sequence of 20-30 amino acids, a cysteine-rich domain (CRD) of approximately 120 amino acids, and a netrin-related motif (NTR) domain. Conserved cysteines of the CRD are indicated by *.


SFRP4 protein is comprised of 346 amino acids with a predicted molecular weight of 39.9 kDa and an actual molecular weight of approximately 50-55 kDa.
SFRP4 belongs to a family of five SFRPs; these proteins fold into two independent domains. The N-terminus contains a secretion signal peptide followed by a ~120 amino acid cysteine-rich domain (CRD). The CRD is 30-50% identical to the extracellular putative Wnt-binding domain of frizzled (Fzd) receptors and is characterized by the presence of ten cysteine residues at conserved positions. These cysteines form a pattern of disulfide bridges. The C-terminal portion of the SFRP protein is characterized by segments of positively charged residues that appear to confer heparin-binding properties in at least two SFRPs (SFRP1 and SFRP3) and contains a netrin-related motif (NTR) with six cysteine residues that most likely form three disulfide bridges. NTR domains with similar features are found in a wide range of unrelated proteins, including Netrin-1, tissue inhibitors of metallo-proteinases (TIMPs), complement proteins and type I procollagen C-proteinase enhancer proteins (PCOLCEs). The six conserved cysteines in the NTR of SFRP4 share a similar spacing to SFRP3, whereas those of the SFRP1/SFRP2/SFRP5 subgroup are distinctively different, indicating a disparity in disulfide bond formation. Uniquely, SFRP4 contains two additional cysteine residues. The overall function of the NTR is unknown, yet there is some evidence that the NTR may also play a role in Wnt binding. This implies that multiple Wnt binding sites may exist on SFRP molecules and/or that SFRPs exhibit differential affinities for Wnt ligands according to the different SFRP conformational and post-translational modifications.


SFRP4 is expressed in various normal tissues including endometrium (specifically stromal cells with higher expression during proliferative phase of menstrual cycle), ovary, kidney, heart, brain, mammary gland, cervix, pancreas, stomach, colon, lung, skeletal muscle, testis, eye, bone, prostate, and liver.


Secreted from cell; extracellular matrix; bound to plasma membrane.


Since SFRPs share a similar CRD with the Fzd family of receptors; it is believed that SFRPs may act as soluble modulators that compete with Fzd to bind the Wnt ligands, thereby altering the Wnt signal. Individual SFRPs also have distinct binding specificity for distinct Wnt ligands. Reports have demonstrated that SFRP4 binds Wnt7a and there is conflicting data for SFRP4 binding to Wnt3a. SFRP4 expression is regulated by estrogen and progesterone and may act as a regulator of adult uterine morphology and function. SFRP4 has been shown to increase apoptosis during ovulation. Transgenic studies have found that SFRP4 decreases bone formation and inhibits osteoblast proliferation by attenuating canonical/beta-catenin-Wnt signaling. SFRP4 reportedly exhibits phosphaturic effects by specifically inhibiting sodium-dependent phosphate uptake.
Atlas Image
CLUSTAL alignment of the 5 human SFRPs.


Of the five human SFRPs (SFRP1, SFRP2, SFRP3, SFRP4, SFRP5), SFRP4 shares most significant homology with SFRP3.



It was reported that the T allele of the SFRP4 gene polymorphism ARG262 (CGC to CGT) of exon4 is associated with decreased bone mineral density in post-menopausal Japanese women.

Implicated in

Entity name
Endometrial Carcinoma
SFRP4 was more frequently down-regulated in (microsatellite instability). MSI cancers as compared with (microsatellite stable) MSS endometrioid endometrial cancers. Expression of SFRP4 is decreased in both low-grade endometrial stromal sarcoma and undifferentiated endometrial sarcoma.
Entity name
Malignant Pleural Mesothelioma
SFRP4 promoter is frequently methylated in this cancer leading to inhibition of expression and is associated with abnormal growth; restoration of SFRP4 results in growth suppression and apoptosis in mesothelioma cell lines.
Entity name
Tumor-induced osteomalacia
Tumor-induced osteomalacia is a disorder in which there is an increase in renal phosphate excretion and a reduction in serum phosphate levels leading to hyperphosphaturia, hypophosphatemia and rickets. SFRP4 is highly expressed in such tumors and functions as a circulating phosphaturic factor that antagonizes renal Wnt-signaling.
Entity name
Breast Cancer
Studies have found evidence for SFRP4 overexpression in breast cancer.
Entity name
Pancreatic Cancer
SFRP4 found to be significantly hypermethylated in the tumors of cancer patients versus matched adjacent tissue controls.
Entity name
Gastric Carcinoma
The SFRP4 was highly methylated in gastric carcinoma samples with greater instance in H. pylori positive patients.
Entity name
Prostate Cancer
SFRP4 is overexpressed in prostate cancers and functions to inhibit cell proliferation and metastatic potential.
Increased expression of membranous SFRP4 is associated with a good prognosis in human localized androgen-dependent prostate cancer, suggesting a role for sFRP4 in early stage disease.
Entity name
B-cell chronic lymphocytic leukemia
SFRP4 was found to be frequently methylated and downregulated in CLL samples.
Entity name
Colorectal Carcinoma
SFRP4 expression was shown to be up-regulated in colorectal cancer.
Entity name
Esophageal Adenocarcinoma
SFRP4 mRNA and protein expression were significantly decreased due to hypermethylation in esophageal adenocarcinoma and Barretts esophagus patients.


Pubmed IDLast YearTitleAuthors
102119961999Differential expression of frpHE: a novel human stromal protein of the secreted frizzled gene family, during the endometrial cycle and malignancy.Abu-Jawdeh G et al
152398382004Microarray profiling of progesterone-regulated endometrial genes during the rhesus monkey secretory phase.Ace CI et al
103471721999Interaction of frizzled related protein (FRP) with Wnt ligands and the frizzled receptor suggests alternative mechanisms for FRP inhibition of Wnt signaling.Bafico A et al
104526071999The NTR module: domains of netrins, secreted frizzled related proteins, and type I procollagen C-proteinase enhancer protein are homologous with tissue inhibitors of metalloproteases.Bányai L et al
129529272003Secreted frizzled-related protein 4 is a potent tumor-derived phosphaturic agent.Berndt T et al
161517912006Secreted frizzled-related protein-4 reduces sodium-phosphate co-transporter abundance and activity in proximal tubule cells.Berndt TJ et al
185289412008Hypermethylation and aberrant expression of secreted frizzled-related protein genes in pancreatic cancer.Bu XM et al
185678052008Secreted frizzled-related protein 4 regulates two Wnt7a signaling pathways and inhibits proliferation in endometrial cancer cells.Carmon KS et al
117419402002Disulfide bond assignments of secreted Frizzled-related protein-1 provide insights about Frizzled homology and netrin modules.Chong JM et al
114523122001Insights into Wnt binding and signalling from the structures of two Frizzled cysteine-rich domains.Dann CE et al
105235161999A secreted frizzled related protein, FrzA, selectively associates with Wnt-1 protein and regulates wnt-1 signaling.Dennis S et al
128152822003The role of sFRP4, a secreted frizzled-related protein, in ovulation.Drake JM et al
163568382006Expression of sFRP-4 and beta-catenin in human colorectal carcinoma.Feng Han Q et al
91926401997Purification and molecular cloning of a secreted, Frizzled-related antagonist of Wnt action.Finch PW et al
120631872002Differential expression of secreted frizzled-related protein 4 in decidual cells during pregnancy.Fujita M et al
157058702005Secreted frizzled-related protein 4 is silenced by hypermethylation and induces apoptosis in beta-catenin-deficient human mesothelioma cells.He B et al
147600842004Membranous expression of secreted frizzled-related protein 4 predicts for good prognosis in localized prostate cancer and inhibits PC3 cellular proliferation in vitro.Horvath LG et al
153071342004Inverse correlation of secreted frizzled-related protein 4 and beta-catenin expression in endometrial stromal sarcomas.Hrzenjak A et al
181585592008DNA methylation profiles of gastric carcinoma characterized by quantitative DNA methylation analysis.Kang GH et al
152210142004Expression of the secreted frizzled-related protein gene family is downregulated in human mesothelioma.Lee AY et al
164239932006CpG island methylation and expression of the secreted frizzled-related protein gene family in chronic lymphocytic leukemia.Liu TH et al
179079182008Osteoblast-targeted expression of Sfrp4 in mice results in low bone mass.Nakanishi R et al
159585452005Gene expression profiling of microsatellite unstable and microsatellite stable endometrial cancers indicates distinct pathways of aberrant signaling.Risinger JI et al
112790072001Localization of disulfide bonds in the frizzled module of Ror1 receptor tyrosine kinase.Roszmusz E et al
173144922006Wnt signaling pathway in mammary gland development and carcinogenesis.Turashvili G et al
106606082000Secreted frizzled-related protein-1 binds directly to Wingless and is a biphasic modulator of Wnt signaling.Uren A et al
174626032007Wnt3a binds to several sFRPs in the nanomolar range.Wawrzak D et al
115533482001Heads or tails: Wnts and anterior-posterior patterning.Yamaguchi TP et al
158251752005Aberrant methylation of secreted frizzled-related protein genes in esophageal adenocarcinoma and Barrett's esophagus.Zou H et al

Other Information

Locus ID:

NCBI: 6424
MIM: 606570
HGNC: 10778
Ensembl: ENSG00000106483


dbSNP: 6424
ClinVar: 6424
TCGA: ENSG00000106483


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Wnt signaling pathwayKEGGko04310
Wnt signaling pathwayKEGGhsa04310

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
193961692009A large-scale genome-wide association study of Asian populations uncovers genetic factors influencing eight quantitative traits.350
166090232006Combination analysis of hypermethylated Wnt-antagonist family genes as a novel epigenetic biomarker panel for bladder cancer detection.53
129529272003Secreted frizzled-related protein 4 is a potent tumor-derived phosphaturic agent.49
231406422012Secreted frizzled-related protein 4 reduces insulin secretion and is overexpressed in type 2 diabetes.42
190405662008The roles of Wnt antagonists Dkk1 and sFRP4 during adipogenesis of human adipose tissue-derived mesenchymal stem cells.39
185921562008Frequent epigenetic inactivation of SFRP genes in hepatocellular carcinoma.37
233266052013The Wnt gatekeeper SFRP4 modulates EMT, cell migration and downstream Wnt signalling in serous ovarian cancer cells.36
208116862010WNT pathway in oral cancer: epigenetic inactivation of WNT-inhibitors.33
180792022008Wnt pathway inhibitors are strongly down-regulated in pituitary tumors.26
157058702005Secreted frizzled-related protein 4 is silenced by hypermethylation and induces apoptosis in beta-catenin-deficient human mesothelioma cells.23


Kendra S Carmon ; David S Loose

SFRP4 (Secreted Frizzled-Related Protein 4)

Atlas Genet Cytogenet Oncol Haematol. 2009-04-01

Online version: