| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
J Biol Chem, Vol. 274, Issue 7, 4266-4272, February 12, 1999
From the Department of Cell and Structural Biology, University of
Illinois, Urbana-Champaign, Urbana, Illinois 61801
The immunosuppressant rapamycin, in complex with
its cellular receptor FKBP12, targets the cellular protein
FKBP12-rapamycin-associated protein/mammalian target of
rapamycin/rapamycin and FKBP12 target 1 (FRAP/mTOR/RAFT1) and
inhibits/delays G1 cell cycle progression in
mammalian cells. As a member of the novel phosphatidylinositol kinase-related kinase family, FRAP's kinase activity is essential for
its signaling function. The FKBP12-rapamycin binding (FRB) domain in
FRAP is also speculated to play an important role in FRAP function and
signaling. However, the biochemical and physiological functions of FRB,
as well as the mechanism for rapamycin inhibition, have been unclear.
The present study focuses on investigation of FRB's role and the
functional relationship between FRB domain and kinase domain in FRAP.
Microinjection of purified FRB protein into human osteosarcoma MG63
cells results in a drastic blockage of the G1 to S cell
cycle progression; such a dominant negative effect is reversed by a
point mutation (Trp2027 
Phe). The same mutation also
abolishes kinase activity of FRAP without affecting ATP binding, and
truncation studies suggest that upstream sequences including FRB are
required for kinase activity in vitro. Given these data, we
propose a model for FRAP function, in which the FRB domain is required
for activation of the kinase domain, possibly through the interaction
with an upstream activator. In addition, our observations provide
direct evidence linking FRAP function to G1 cell cycle progression.
This article has been cited by other articles:
|
|
 |
|
  L. J. Reichling, C. S. Lebakken, S. M. Riddle, K. L. Vedvik, M. B. Robers, L. M. Kopp, R. Bruinsma, and K. W. Vogel Pharmacological Characterization of Purified Recombinant mTOR FRB-Kinase Domain Using Fluorescence-Based Assays J Biomol Screen, March 1, 2008; 13(3): 238 - 244. [Abstract] [PDF]
|
|
|
|
 |
|
 S. R. Edwards and T. J. Wandless The Rapamycin-binding Domain of the Protein Kinase Mammalian Target of Rapamycin Is a Destabilizing Domain J. Biol. Chem., May 4, 2007; 282(18): 13395 - 13401. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Gossrau, J. Thiele, R. Konang, T. Schmandt, and O. Brustle Bone Morphogenetic Protein-Mediated Modulation of Lineage Diversification During Neural Differentiation of Embryonic Stem Cells Stem Cells, April 1, 2007; 25(4): 939 - 949. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Morita, A. Yamashita, I. Kashima, K. Ogata, S. Ishiura, and S. Ohno Distant N- and C-terminal Domains Are Required for Intrinsic Kinase Activity of SMG-1, a Critical Component of Nonsense-mediated mRNA Decay J. Biol. Chem., March 16, 2007; 282(11): 7799 - 7808. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Gong, C. S. Park, N. R. Abbassi, and S.-J. Tang Roles of Glutamate Receptors and the Mammalian Target of Rapamycin (mTOR) Signaling Pathway in Activity-dependent Dendritic Protein Synthesis in Hippocampal Neurons J. Biol. Chem., July 7, 2006; 281(27): 18802 - 18815. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. A. Bachmann, J.-H. Kim, A.-L. Wu, I.-H. Park, and J. Chen A Nuclear Transport Signal in Mammalian Target of Rapamycin Is Critical for Its Cytoplasmic Signaling to S6 Kinase 1 J. Biol. Chem., March 17, 2006; 281(11): 7357 - 7363. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Zhang, C. J. Billington Jr., D. Pan, and T. P. Neufeld Drosophila Target of Rapamycin Kinase Functions as a Multimer Genetics, January 1, 2006; 172(1): 355 - 362. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. C. Fingar, C. J. Richardson, A. R. Tee, L. Cheatham, C. Tsou, and J. Blenis mTOR Controls Cell Cycle Progression through Its Cell Growth Effectors S6K1 and 4E-BP1/Eukaryotic Translation Initiation Factor 4E Mol. Cell. Biol., January 1, 2004; 24(1): 200 - 216. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. E. Harris and J. C. Lawrence Jr. TOR Signaling Sci. Signal., December 9, 2003; 2003(212): re15 - re15. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. M. Sievers New Antiproliferative Immunosuppressive Agents Journal of Pharmacy Practice, December 1, 2003; 16(6): 401 - 413. [Abstract] [PDF]
|
|
|
|
 |
|
 P. Rajan, D. M. Panchision, L. F. Newell, and R. D.G. McKay BMPs signal alternately through a SMAD or FRAP-STAT pathway to regulate fate choice in CNS stem cells J. Cell Biol., June 9, 2003; 161(5): 911 - 921. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. P. McMahon, K. M. Choi, T.-A. Lin, R. T. Abraham, and J. C. Lawrence Jr. The Rapamycin-Binding Domain Governs Substrate Selectivity by the Mammalian Target of Rapamycin Mol. Cell. Biol., November 1, 2002; 22(21): 7428 - 7438. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I.-H. Park, R. Bachmann, H. Shirazi, and J. Chen Regulation of Ribosomal S6 Kinase 2 by Mammalian Target of Rapamycin J. Biol. Chem., August 23, 2002; 277(35): 31423 - 31429. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Hohmann Osmotic Stress Signaling and Osmoadaptation in Yeasts Microbiol. Mol. Biol. Rev., June 1, 2002; 66(2): 300 - 372. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Fang, M. Vilella-Bach, R. Bachmann, A. Flanigan, and J. Chen Phosphatidic Acid-Mediated Mitogenic Activation of mTOR Signaling Science, November 30, 2001; 294(5548): 1942 - 1945. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. E. Hentges, B. Sirry, A.-C. Gingeras, D. Sarbassov, N. Sonenberg, D. Sabatini, and A. S. Peterson FRAP/mTOR is required for proliferation and patterning during embryonic development in the mouse PNAS, November 9, 2001; (2001) 241184198. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. M. Woltman, J. W. de Fijter, S. W. A. Kamerling, S. W. van der Kooij, L. C. Paul, M. R. Daha, and C. van Kooten Rapamycin induces apoptosis in monocyte- and CD34-derived dendritic cells but not in monocytes and macrophages Blood, July 1, 2001; 98(1): 174 - 180. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. E. Kim and J. Chen Cytoplasmic-nuclear shuttling of FKBP12-rapamycin-associated protein is involved in rapamycin-sensitive signaling and translation initiation PNAS, December 8, 2000; (2000) 11511898. [Abstract] [Full Text]
|
|
|
|
 |
|
 H. Zhang, J. P. Stallock, J. C. Ng, C. Reinhard, and T. P. Neufeld Regulation of cellular growth by the Drosophila target of rapamycin dTOR Genes & Dev., November 1, 2000; 14(21): 2712 - 2724. [Abstract] [Full Text]
|
|
|
|
|
|
B. K. Law, P. Norgaard, and H. L. Moses Farnesyltransferase Inhibitor Induces Rapid Growth Arrest and Blocks p70s6k Activation by Multiple Stimuli J. Biol. Chem., April 6, 2000; 275(15): 10796 - 10801. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Denning, L. Jamieson, L. E. Maquat, E. A. Thompson, and A. P. Fields Cloning of a Novel Phosphatidylinositol Kinase-related Kinase. CHARACTERIZATION OF THE HUMAN SMG-1 RNA SURVEILLANCE PROTEIN J. Biol. Chem., June 15, 2001; 276(25): 22709 - 22714. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Erbay and J. Chen The Mammalian Target of Rapamycin Regulates C2C12 Myogenesis via a Kinase-independent Mechanism J. Biol. Chem., September 21, 2001; 276(39): 36079 - 36082. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. K. Law, M. E. Waltner-Law, A. J. Entingh, A. Chytil, M. E. Aakre, P. Norgaard, and H. L. Moses Salicylate-induced Growth Arrest Is Associated with Inhibition of p70s6k and Down-regulation of c-Myc, Cyclin D1, Cyclin A, and Proliferating Cell Nuclear Antigen J. Biol. Chem., December 1, 2000; 275(49): 38261 - 38267. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Rohde, J. Heitman, and M. E. Cardenas The TOR Kinases Link Nutrient Sensing to Cell Growth J. Biol. Chem., March 23, 2001; 276(13): 9583 - 9586. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. E. Kim and J. Chen Cytoplasmic-nuclear shuttling of FKBP12-rapamycin-associated protein is involved in rapamycin-sensitive signaling and translation initiation PNAS, December 19, 2000; 97(26): 14340 - 14345. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. E. Hentges, B. Sirry, A.-C. Gingeras, D. Sarbassov, N. Sonenberg, D. Sabatini, and A. S. Peterson FRAP/mTOR is required for proliferation and patterning during embryonic development in the mouse PNAS, November 20, 2001; 98(24): 13796 - 13801. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| All ASBMB Journals | Molecular and Cellular Proteomics |
| Journal of Lipid Research | ASBMB Today |
