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Gene Review

FRAT1  -  frequently rearranged in advanced T-cell...

Homo sapiens

Synonyms: FRAT-1, Frequently rearranged in advanced T-cell lymphomas 1, Proto-oncogene FRAT1
 
 
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Disease relevance of FRAT1

 

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

 

Anatomical context of FRAT1

 

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

References

  1. Characterization and tissue-specific expression of human GSK-3-binding proteins FRAT1 and FRAT2. Freemantle, S.J., Portland, H.B., Ewings, K., Dmitrovsky, F., DiPetrillo, K., Spinella, M.J., Dmitrovsky, E. Gene (2002) [Pubmed]
  2. Molecular cloning and expression of proto-oncogene FRAT1 in human cancer. Saitoh, T., Mine, T., Katoh, M. Int. J. Oncol. (2002) [Pubmed]
  3. Structural basis for recruitment of glycogen synthase kinase 3beta to the axin-APC scaffold complex. Dajani, R., Fraser, E., Roe, S.M., Yeo, M., Good, V.M., Thompson, V., Dale, T.C., Pearl, L.H. EMBO J. (2003) [Pubmed]
  4. Axin and Frat1 interact with dvl and GSK, bridging Dvl to GSK in Wnt-mediated regulation of LEF-1. Li, L., Yuan, H., Weaver, C.D., Mao, J., Farr, G.H., Sussman, D.J., Jonkers, J., Kimelman, D., Wu, D. EMBO J. (1999) [Pubmed]
  5. Casein kinase I epsilon enhances the binding of Dvl-1 to Frat-1 and is essential for Wnt-3a-induced accumulation of beta-catenin. Hino, S., Michiue, T., Asashima, M., Kikuchi, A. J. Biol. Chem. (2003) [Pubmed]
  6. FRAT1 and FRAT2, clustered in human chromosome 10q24.1 region, are up-regulated in gastric cancer. Saitoh, T., Katoh, M. Int. J. Oncol. (2001) [Pubmed]
  7. FRAT1 peptide decreases Abeta production in swAPP(751) cells. Li, B., Ryder, J., Su, Y., Zhou, Y., Liu, F., Ni, B. FEBS Lett. (2003) [Pubmed]
  8. Proteomic analysis of the proliferative and secretory phases of the human endometrium: protein identification and differential protein expression. DeSouza, L., Diehl, G., Yang, E.C., Guo, J., Rodrigues, M.J., Romaschin, A.D., Colgan, T.J., Siu, K.W. Proteomics (2005) [Pubmed]
  9. Molecular cloning and characterization of FRAT2, encoding a positive regulator of the WNT signaling pathway. Saitoh, T., Moriwaki, J., Koike, J., Takagi, A., Miwa, T., Shiokawa, K., Katoh, M. Biochem. Biophys. Res. Commun. (2001) [Pubmed]
  10. A GSK3-binding peptide from FRAT1 selectively inhibits the GSK3-catalysed phosphorylation of axin and beta-catenin. Thomas, G.M., Frame, S., Goedert, M., Nathke, I., Polakis, P., Cohen, P. FEBS Lett. (1999) [Pubmed]
  11. FRAT1, a substrate-specific regulator of glycogen synthase kinase-3 activity, is a cellular substrate of protein kinase A. Hagen, T., Cross, D.A., Culbert, A.A., West, A., Frame, S., Morrice, N., Reith, A.D. J. Biol. Chem. (2006) [Pubmed]
  12. Inhibition of glycogen synthase kinase-3 represses androgen receptor activity and prostate cancer cell growth. Mazor, M., Kawano, Y., Zhu, H., Waxman, J., Kypta, R.M. Oncogene (2004) [Pubmed]
  13. Tissue microarray analysis of human FRAT1 expression and its correlation with the subcellular localisation of beta-catenin in ovarian tumours. Wang, Y., Hewitt, S.M., Liu, S., Zhou, X., Zhu, H., Zhou, C., Zhang, G., Quan, L., Bai, J., Xu, N. Br. J. Cancer (2006) [Pubmed]
 
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