Originally published as Genetics Published Articles Ahead of Print on October 11, 2005.

Genetics, Vol. 172, 355-362, January 2006, Copyright © 2006
doi:10.1534/genetics.105.051979

Drosophila Target of Rapamycin Kinase Functions as a Multimer

Yong Zhang^*, Charles J. Billington, Jr., Duojia Pan^* and Thomas P. Neufeld^,1

^* Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205-2185 and Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, Minnesota 55455

¹ Corresponding author: Department of Genetics, Cell Biology and Development, University of Minnesota, 6-160 Jackson Hall, 321 Church St. S.E., Minneapolis, MN 55455.
E-mail: neufeld{at}med.umn.edu

Target of rapamycin (TOR) is a conserved regulator of cell growth and metabolism that integrates energy, growth factor, and nutrient signals. The 280-kDa TOR protein functions as the catalytic component of two large multiprotein complexes and consists of an N-terminal HEAT-repeat domain and a C-terminal Ser/Thr kinase domain. Here we describe an allelic series of mutations in the Drosophila Tor gene and show that combinations of mutations in the HEAT and kinase domains of TOR display the rare genetic phenomenon of intragenic complementation, in which two or more defective proteins assemble to form a functional multimer. We present biochemical evidence that TOR self-associates in vivo and show that this multimerization is unaffected by positive or negative signals upstream of TOR. Consistent with multimerization of TOR, recessive mutations in the HEAT and kinase domains can dominantly interfere with wild-type TOR function in cells lacking TSC1 or TSC2. TOR multimerization thus partially accounts for the high apparent molecular weight of TOR complexes and offers novel therapeutic strategies for pathologies stemming from TOR hyperactivity.

This article has been cited by other articles:

				G. Juhasz, J. H. Hill, Y. Yan, M. Sass, E. H. Baehrecke, J. M. Backer, and T. P. Neufeld The class III PI(3)K Vps34 promotes autophagy and endocytosis but not TOR signaling in Drosophila J. Cell Biol., October 17, 2008; 181(4): 655 - 666. [Abstract] [Full Text] [PDF]

				S. Diaz-Troya, F. J. Florencio, and J. L. Crespo Target of Rapamycin and LST8 Proteins Associate with Membranes from the Endoplasmic Reticulum in the Unicellular Green Alga Chlamydomonas reinhardtii Eukaryot. Cell, February 1, 2008; 7(2): 212 - 222. [Abstract] [Full Text] [PDF]

				L. Wang, T. E. Harris, R. A. Roth, and J. C. Lawrence Jr PRAS40 Regulates mTORC1 Kinase Activity by Functioning as a Direct Inhibitor of Substrate Binding J. Biol. Chem., July 6, 2007; 282(27): 20036 - 20044. [Abstract] [Full Text] [PDF]

				A. Reinke, J. C.-Y. Chen, S. Aronova, and T. Powers Caffeine Targets TOR Complex I and Provides Evidence for a Regulatory Link between the FRB and Kinase Domains of Tor1p J. Biol. Chem., October 20, 2006; 281(42): 31616 - 31626. [Abstract] [Full Text] [PDF]

				L. Wang, C. J. Rhodes, and J. C. Lawrence Jr. Activation of Mammalian Target of Rapamycin (mTOR) by Insulin Is Associated with Stimulation of 4EBP1 Binding to Dimeric mTOR Complex 1 J. Biol. Chem., August 25, 2006; 281(34): 24293 - 24303. [Abstract] [Full Text] [PDF]

				E. E. Griffin and D. C. Chan Domain Interactions within Fzo1 Oligomers Are Essential for Mitochondrial Fusion J. Biol. Chem., June 16, 2006; 281(24): 16599 - 16606. [Abstract] [Full Text] [PDF]

International Access Link

Online ISSN: 1943-2361  Print ISSN: 0016-6731
Copyright 2009 by the Genetics Society of America
phone: 412-268-1812   fax: 412-268-1813   email: genetics-gsa{at}andrew.cmu.edu