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Gene Review

MTOR  -  mechanistic target of rapamycin...

Homo sapiens

Synonyms: FK506-binding protein 12-rapamycin complex-associated protein 1, FKBP12-rapamycin complex-associated protein, FLJ44809, FRAP, FRAP1, ...
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Disease relevance of FRAP1

  • Exposure either to hypoxia or the EGFR inhibitors under normoxic conditions resulted in the dephosphorylation of ribosomal protein S6, a player in the energy and nutrient-sensing pathway governed by mammalian target-of-rapamycin (mTOR) [1].
  • Modulation of hypoxia-inducible factor 1alpha expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics [2].
  • The structure of the FRB domain of FRAP clarifies both rapamycin-independent and -dependent effects observed for mutants of FRAP and its homologs in the family of proteins related to the ataxia-telangiectasia mutant gene product, and it illustrates how a small cell-permeable molecule can mediate protein dimerization [3].
  • Inhibition of mTOR/FRAP by rapamycin reduces apoptosis in several paradigms of syncytium-dependent death, including in primary CD4(+) lymphoblasts infected by HIV-1 [4].
  • Capture of the long-lived interaction complex allows the isolation of phage bearing cognate interaction pairs, as we demonstrate for a range of interactions, including Ab-antigen pairs and the rapamycin-dependent interaction of FKBP-12 and FRAP [5].
  • These findings collectively suggest that the mTOR pathway is positively regulated by Notch in T-ALL cells [6].

High impact information on FRAP1


Chemical compound and disease context of FRAP1


Biological context of FRAP1

  • ANGPTL7 gene at human chromosome 1p36.22 was located within intron 28 of FRAP1 gene encoding mTOR protein [14].
  • RAFT1 phosphorylates p70(S6k) on Thr-389, a residue whose phosphorylation is rapamycin-sensitive in vivo and necessary for S6 kinase activity [15].
  • Further investigation by altering FRAP's nuclear shuttling activity with exogenous nuclear import and export signals has yielded results that are consistent with a direct link between nuclear shuttling of FRAP and mitogenic stimulation of p70(s6k) activation and 4E-BP1 phosphorylation [16].
  • The FKBP12-rapamycin-associated protein (FRAP; also called RAFT1/mTOR) regulates translation initiation and entry into the cell cycle [17].
  • Transfer of such activation loop sequences from class II PI3Ks, class III PI3Ks, and a related mammalian target of rapamycin (FRAP) into p110alpha turns the lipid substrate specificity of the resulting hybrid protein into that of the donor protein, while leaving the protein kinase activity unaffected [18].

Anatomical context of FRAP1

  • Collectively, our data suggest that the FRAP-controlled p70 ribosomal S6 kinase is an essential component of a DNA damage-dependent, but not of the interleukin-1/cell membrane receptor-dependent signaling [19].
  • Factors Controlling Fibroblast Growth Factor Receptor-1's Cytoplasmic Trafficking and Its Regulation as Revealed by FRAP Analysis [20].
  • FKBP12-rapamycin-associated protein or mammalian target of rapamycin (FRAP/mTOR) localization in the endoplasmic reticulum and the Golgi apparatus [21].
  • FKBP12-rapamycin-associated protein (FRAP) or mammalian target of rapamycin (mTOR) and its effector proteins form a critical signaling pathway that regulates eukaryotic cell growth and proliferation [21].
  • The karyotypic abnormalities in these cell lines were exploited as chromosomal landmarks; we could thus show that the telomere to centromere gene order was PTPRZ2-(MBP-1/ENO1/ENO1L1)-(C1orf1/XBX1)-+ ++FRAP2 [22].

Associations of FRAP1 with chemical compounds

  • Inhibition of FRAP nuclear export by LMB coincides with diminished p70(s6k) activation and 4E-BP1 phosphorylation [16].
  • FKBP12-rapamycin-associated protein (FRAP) autophosphorylates at serine 2481 under translationally repressive conditions [23].
  • Importantly, only FRAP-dependent IRS-1(511-772) serine phosphorylation inhibited by 50% subsequent JAK1-dependent tyrosine phosphorylation of IRS-1 [24].
  • We now show that the FRAP Ser2035-->Ala mutant displays similar binding affinity when compared with the wild-type protein, whereas all other mutations at this site, including mimics of phosphoserine, abolish binding, presumably due to either unfavorable steric interactions or induced conformational changes [25].
  • Treatment of cells with rapamycin, a selective FRAP Inhibitor, inhibited basal p70s6K kinase activity and induced dephosphorylation of p70s6K and 4E-BP1 [26].
  • Long-term pretreatment with the mTOR inhibitor rapamycin significantly blocked both mTOR-raptor and mTOR-rictor complex formation [27].

Physical interactions of FRAP1

  • Here we isolate a mammalian FKBP-rapamycin-associated protein (FRAP) whose binding to structural variants of rapamycin complexed to FKBP12 correlates with the ability of these ligands to inhibit cell-cycle progression [28].

Enzymatic interactions of FRAP1


Regulatory relationships of FRAP1

  • We present evidence that FRAP controls 4E-BP1 and p70(s6k) phosphorylation indirectly by restraining a phosphatase [17].
  • The mechanism by which PI3K and FRAP cooperate to induce p70S6K activation remains unclear [29].

Other interactions of FRAP1


Analytical, diagnostic and therapeutic context of FRAP1


  1. Inhibition of epidermal growth factor receptor signaling protects human malignant glioma cells from hypoxia-induced cell death. Steinbach, J.P., Klumpp, A., Wolburg, H., Weller, M. Cancer Res. (2004) [Pubmed]
  2. Modulation of hypoxia-inducible factor 1alpha expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics. Zhong, H., Chiles, K., Feldser, D., Laughner, E., Hanrahan, C., Georgescu, M.M., Simons, J.W., Semenza, G.L. Cancer Res. (2000) [Pubmed]
  3. Structure of the FKBP12-rapamycin complex interacting with the binding domain of human FRAP. Choi, J., Chen, J., Schreiber, S.L., Clardy, J. Science (1996) [Pubmed]
  4. Human immunodeficiency virus 1 envelope glycoprotein complex-induced apoptosis involves mammalian target of rapamycin/FKBP12-rapamycin-associated protein-mediated p53 phosphorylation. Castedo, M., Ferri, K.F., Blanco, J., Roumier, T., Larochette, N., Barretina, J., Amendola, A., Nardacci, R., Métivier, D., Este, J.A., Piacentini, M., Kroemer, G. J. Exp. Med. (2001) [Pubmed]
  5. Isolation of receptor-ligand pairs by capture of long-lived multivalent interaction complexes. de Wildt, R.M., Tomlinson, I.M., Ong, J.L., Holliger, P. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  6. Notch signals positively regulate activity of the mTOR pathway in T-cell acute lymphoblastic leukemia. Chan, S.M., Weng, A.P., Tibshirani, R., Aster, J.C., Utz, P.J. Blood (2007) [Pubmed]
  7. Golgi membranes remain segregated from the endoplasmic reticulum during mitosis in mammalian cells. Pecot, M.Y., Malhotra, V. Cell (2004) [Pubmed]
  8. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Kim, D.H., Sarbassov, D.D., Ali, S.M., King, J.E., Latek, R.R., Erdjument-Bromage, H., Tempst, P., Sabatini, D.M. Cell (2002) [Pubmed]
  9. DNA-dependent protein kinase catalytic subunit: a relative of phosphatidylinositol 3-kinase and the ataxia telangiectasia gene product. Hartley, K.O., Gell, D., Smith, G.C., Zhang, H., Divecha, N., Connelly, M.A., Admon, A., Lees-Miller, S.P., Anderson, C.W., Jackson, S.P. Cell (1995) [Pubmed]
  10. Control of p70 s6 kinase by kinase activity of FRAP in vivo. Brown, E.J., Beal, P.A., Keith, C.T., Chen, J., Shin, T.B., Schreiber, S.L. Nature (1995) [Pubmed]
  11. Regulation of 4E-BP1 phosphorylation: a novel two-step mechanism. Gingras, A.C., Gygi, S.P., Raught, B., Polakiewicz, R.D., Abraham, R.T., Hoekstra, M.F., Aebersold, R., Sonenberg, N. Genes Dev. (1999) [Pubmed]
  12. 4-Hydroxy estradiol but not 2-hydroxy estradiol induces expression of hypoxia-inducible factor 1alpha and vascular endothelial growth factor A through phosphatidylinositol 3-kinase/Akt/FRAP pathway in OVCAR-3 and A2780-CP70 human ovarian carcinoma cells. Gao, N., Nester, R.A., Sarkar, M.A. Toxicol. Appl. Pharmacol. (2004) [Pubmed]
  13. Akt-dependent regulation of NF-{kappa}B is controlled by mTOR and Raptor in association with IKK. Dan, H.C., Cooper, M.J., Cogswell, P.C., Duncan, J.A., Ting, J.P., Baldwin, A.S. Genes Dev. (2008) [Pubmed]
  14. Comparative integromics on Angiopoietin family members. Katoh, Y., Katoh, M. Int. J. Mol. Med. (2006) [Pubmed]
  15. RAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E-BP1. Burnett, P.E., Barrow, R.K., Cohen, N.A., Snyder, S.H., Sabatini, D.M. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  16. Cytoplasmic-nuclear shuttling of FKBP12-rapamycin-associated protein is involved in rapamycin-sensitive signaling and translation initiation. Kim, J.E., Chen, J. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  17. Protein phosphatase 2A interacts with the 70-kDa S6 kinase and is activated by inhibition of FKBP12-rapamycinassociated protein. Peterson, R.T., Desai, B.N., Hardwick, J.S., Schreiber, S.L. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  18. Activation loop sequences confer substrate specificity to phosphoinositide 3-kinase alpha (PI3Kalpha ). Functions of lipid kinase-deficient PI3Kalpha in signaling. Pirola, L., Zvelebil, M.J., Bulgarelli-Leva, G., Van Obberghen, E., Waterfield, M.D., Wymann, M.P. J. Biol. Chem. (2001) [Pubmed]
  19. Activation of p70 ribosomal protein S6 kinase is an essential step in the DNA damage-dependent signaling pathway responsible for the ultraviolet B-mediated increase in interstitial collagenase (MMP-1) and stromelysin-1 (MMP-3) protein levels in human dermal fibroblasts. Brenneisen, P., Wenk, J., Wlaschek, M., Krieg, T., Scharffetter-Kochanek, K. J. Biol. Chem. (2000) [Pubmed]
  20. Factors Controlling Fibroblast Growth Factor Receptor-1's Cytoplasmic Trafficking and Its Regulation as Revealed by FRAP Analysis. Dunham-Ems, S.M., Pudavar, H.E., Myers, J.M., Maher, P.A., Prasad, P.N., Stachowiak, M.K. Mol. Biol. Cell (2006) [Pubmed]
  21. FKBP12-rapamycin-associated protein or mammalian target of rapamycin (FRAP/mTOR) localization in the endoplasmic reticulum and the Golgi apparatus. Drenan, R.M., Liu, X., Bertram, P.G., Zheng, X.F. J. Biol. Chem. (2004) [Pubmed]
  22. Molecular cloning and expression analysis of five novel genes in chromosome 1p36. Onyango, P., Lubyova, B., Gardellin, P., Kurzbauer, R., Weith, A. Genomics (1998) [Pubmed]
  23. FKBP12-rapamycin-associated protein (FRAP) autophosphorylates at serine 2481 under translationally repressive conditions. Peterson, R.T., Beal, P.A., Comb, M.J., Schreiber, S.L. J. Biol. Chem. (2000) [Pubmed]
  24. Frap-dependent serine phosphorylation of IRS-1 inhibits IRS-1 tyrosine phosphorylation. Hartman, M.E., Villela-Bach, M., Chen, J., Freund, G.G. Biochem. Biophys. Res. Commun. (2001) [Pubmed]
  25. Identification of an 11-kDa FKBP12-rapamycin-binding domain within the 289-kDa FKBP12-rapamycin-associated protein and characterization of a critical serine residue. Chen, J., Zheng, X.F., Brown, E.J., Schreiber, S.L. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  26. Regulation of cell growth and cyclin D1 expression by the constitutively active FRAP-p70s6K pathway in human pancreatic cancer cells. Grewe, M., Gansauge, F., Schmid, R.M., Adler, G., Seufferlein, T. Cancer Res. (1999) [Pubmed]
  27. HLA class I antibody-mediated endothelial cell proliferation via the mTOR pathway. Jindra, P.T., Jin, Y.P., Rozengurt, E., Reed, E.F. J. Immunol. (2008) [Pubmed]
  28. A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Brown, E.J., Albers, M.W., Shin, T.B., Ichikawa, K., Keith, C.T., Lane, W.S., Schreiber, S.L. Nature (1994) [Pubmed]
  29. A new role for the p85-phosphatidylinositol 3-kinase regulatory subunit linking FRAP to p70 S6 kinase activation. Gonzalez-Garcia, A., Garrido, E., Hernandez, C., Alvarez, B., Jimenez, C., Cantrell, D.A., Pullen, N., Carrera, A.C. J. Biol. Chem. (2002) [Pubmed]
  30. Serine phosphorylation and maximal activation of STAT3 during CNTF signaling is mediated by the rapamycin target mTOR. Yokogami, K., Wakisaka, S., Avruch, J., Reeves, S.A. Curr. Biol. (2000) [Pubmed]
  31. Ionizing radiation enhances double-strand-break repair in rapamycin-treated ataxia telangiectasia lymphoblasts. Sikpi, M.O., Wang, Y. Int. J. Radiat. Biol. (2000) [Pubmed]
  32. The 400 kDa subunit of the PCAF histone acetylase complex belongs to the ATM superfamily. Vassilev, A., Yamauchi, J., Kotani, T., Prives, C., Avantaggiati, M.L., Qin, J., Nakatani, Y. Mol. Cell (1998) [Pubmed]
  33. Monitoring protein-protein interactions in intact eukaryotic cells by beta-galactosidase complementation. Rossi, F., Charlton, C.A., Blau, H.M. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  34. Assignment of the human FKBP12-rapamycin-associated protein (FRAP) gene to chromosome 1p36 by fluorescence in situ hybridization. Moore, P.A., Rosen, C.A., Carter, K.C. Genomics (1996) [Pubmed]
  35. Three separable domains regulate GTP-dependent association of H-ras with the plasma membrane. Rotblat, B., Prior, I.A., Muncke, C., Parton, R.G., Kloog, Y., Henis, Y.I., Hancock, J.F. Mol. Cell. Biol. (2004) [Pubmed]
  36. Photodynamic therapy on keloid fibroblasts in tissue-engineered keratinocyte-fibroblast co-culture. Chiu, L.L., Sun, C.H., Yeh, A.T., Torkian, B., Karamzadeh, A., Tromberg, B., Wong, B.J. Lasers in surgery and medicine. (2005) [Pubmed]
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