Disease relevance of FRAT1

• It exhibits appreciable amino acid identity to FRAT1 (77%) which was initially isolated as frequently being overexpressed in a murine leukemia virus insertion model in murine tumors [1].
• FRAT1 and FRAT2 mRNAs are up-regulated together in a gastric cancer cell line TMK1, and also in 2 out of 10 cases of primary gastric cancer [2].
• Expression of FRAT1 mRNA in MCF-7 cells derived from breast cancer was down-regulated by beta-estradiol [2].
• FRAT1 mRNA was almost ubiquitously expressed in human pancreatic cancer cell lines [2].
• Expression level of FRAT1 mRNA was relatively higher in esophageal cancer cell lines TE2, TE3, TE4, a cervical cancer cell line SKG-IIIa, and breast cancer cell lines MCF-7 and T-47D [2].

High impact information on FRAT1

• Detailed comparison of the axin and FRAT GSK3beta complexes allows the generation of highly specific mutations, which abrogate binding of one or the other [3].
• Similarly, the Frat1 homolog GBP binds Xenopus Dishevelled in an interaction that requires GSK [4].
• Casein kinase I epsilon enhances the binding of Dvl-1 to Frat-1 and is essential for Wnt-3a-induced accumulation of beta-catenin [5].
• The amino acid region 228-250 of Dvl-1 was necessary for its binding to Frat-1, and the interaction of Dvl-1 with Frat-1 was enhanced by CKI epsilon [5].
• Both proteins also activated the transcriptional activity of T-cell factor-4 (Tcf-4) synergistically in human embryonic kidney 293 cells, but coexpression of Dvl-1-(Delta 228-250), which lacks the amino acid region 228-250 from Dvl-1, and Frat-1 did not [5].

Biological context of FRAT1

• The Gln57-His58 FRAT1 allele isolated in this study was also identified in human genome draft sequences [2].
• Here, we isolated FRAT1 cDNA (AB074890), which showed two amino-acid substitutions (Gln57X and His58Asp) compared with human FRAT1 cDNA previously reported by another group (U58975) [2].
• Both hFRAT1 and hFRAT2 are intronless genes localized to the same portion of chromosome 10q24.1 and separated by only 10.7 kb [1].
• Here, we found that FRAT1 and FRAT2 genes were clustered in the human chromosome 10q24.1 region [6].
• Up-regulation of FRAT1 and FRAT2 in gastric cancer might lead to carcinogenesis through activation of WNT--beta-catenin--TCF signaling pathway [6].

Anatomical context of FRAT1

• When transiently overexpressed in COS-1 cells, the FRAT proteins were detected in the cytosol and concentrated in the nucleus [1].
• This treatment had no appreciable effect on FRAT levels in two other RA-sensitive cell lines that were not of germ cell tumor origin [1].
• The 2.7-kb FRAT1 mRNA was relatively highly expressed in fetal brain, adult spleen, pancreas, HeLa S3 (cervical cancer), and K-562 (chronic myelogenous leukemia) [6].
• Frequently rearranged in advanced T-cell lymphomas 1 (FRAT1) protein is a negative regulator of GSK3alpha/beta kinase activity [7].
• The two proteins with unquestionable differential expressions in the secretory endometrium are: glutamate NMDA receptor subunit zeta 1 precursor and FRAT1 [8].

Associations of FRAT1 with chemical compounds

• Expression level of FRAT1 mRNA was not significantly changed after all-trans retinoic-acid treatment in NT2 cells with the potential of neuronal differentiation [2].
• FRAT2 and FRAT1 were more homologous in the acidic domain (96% identity), the proline-rich domain (92% identity), and the GSK-3beta binding domain (100% identity) [9].

Physical interactions of FRAT1

• Depletion of CKI epsilon by double-stranded RNA interference in HeLa S3 cells led to the inhibition of Wnt-3a-induced phosphorylation of Dvl and the binding of Dvl-1 to Frat-1 [5].
• Frequently rearranged in advanced T-cell lymphomas 1 (FRAT1) is a mammalian homologue of a GSK3-binding protein (GBP), which appears to play a key role in the correct establishment of the dorsal-ventral axis in Xenopus laevis [10].
• FRAT1 positively regulates the WNT signaling pathway by stabilizing beta-catenin through the association with glycogen synthase kinase-3beta [9].

Regulatory relationships of FRAT1

• These results indicate that CKI epsilon-dependent phosphorylation of Dvl enhances the formation of a complex of Dvl-1 with Frat-1 and that this complex leads to the activation of the Wnt signaling pathway [5].
• To examine whether direct inhibition of GSK3alpha/beta kinase activity can lower Abeta production, a FRAT1 peptide was expressed in swAPP(751) cells that produce high levels of Abeta [7].
• PKA phosphorylates FRAT1 in vitro as well as in intact cells and may play a role in regulating the inhibitory activity of FRAT1 toward GSK-3 [11].

Other interactions of FRAT1

• Characterization and tissue-specific expression of human GSK-3-binding proteins FRAT1 and FRAT2 [1].
• Coexpression of Dvl-1 and Frat-1 caused accumulation of beta-catenin synergistically in L cells [5].
• We demonstrate that Dvl-1, casein kinase I epsilon (CKI epsilon), and Frat-1 activate the Wnt signaling pathway cooperatively [5].
• A second GSK-3-binding protein, FRAT, also inhibited AR transcriptional activity, as did the GSK-3 inhibitors SB216763 and SB415286 [12].
• FRAT1 peptide decreases Abeta production in swAPP(751) cells [7].

Analytical, diagnostic and therapeutic context of FRAT1

• Molecular cloning and expression of proto-oncogene FRAT1 in human cancer [2].
• Tissue microarray analysis of human FRAT1 expression and its correlation with the subcellular localisation of beta-catenin in ovarian tumours [13].
• In this study, we developed in situ hybridisation probes to evaluate the presence of FRAT1 and used an anti-beta-catenin antibody to evaluate by immunohistochemistry the expression levels and subcellular localisation of beta-catenin in ovarian cancer tissue microarrays [13].

References