Human Molecular Genetics, 2001, Vol. 10, No. 25 2889-2898
© 2001 Oxford University Press
TSC2 missense mutations inhibit tuberin phosphorylation and prevent formation of the tuberin–hamartin complex
Department of Clinical Genetics, Erasmus University, 3015 GE Rotterdam, The Netherlands
Tuberous sclerosis (TSC) is an autosomal dominant disorder characterized by a broad phenotypic spectrum that includes seizures, mental retardation, renal dysfunction and dermatological abnormalities. Inactivating mutations to either of the TSC1 and TSC2 tumour suppressor genes are responsible for the disease. TSC1 and TSC2 encode two large novel proteins called hamartin and tuberin, respectively. Hamartin and tuberin interact directly with each other and it has been reported that tuberin may act as a chaperone, preventing hamartin self-aggregation and maintaining the tuberin–hamartin complex in a soluble form. In this study, the ability of tuberin to act as a chaperone for hamartin was used to investigate the tuberin–hamartin interaction in more detail. A domain within tuberin necessary for the chaperone function was identified, and the effects of TSC2 missense mutations on the tuberin–hamartin interaction were investigated to allow specific residues within the central domain of tuberin that are important for the interaction with hamartin to be pin-pointed. In addition, the results confirm that phosphorylation may play an important role in the formation of the tuberin–hamartin complex. Although mutations that prevent tuberin tyrosine phosphorylation also inhibit tuberin–hamartin binding and the chaperone function, our results indicate that only hamartin is phosphorylated in the tuberin–hamartin complex.
+ To whom correspondence should be addressed. Tel: +31 10 4087357; Fax: +31 10 4089489; Email: nellist@kgen.fgg.eur.nl
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  G. Ramantani, P. Niggemann, G. Hahn, A. Nake, R. Fahsold, and M. A. Lee-Kirsch Unusual Radiological Presentation of Tuberous Sclerosis Complex With Leptomeningeal Angiomatosis Associated With a Hypomorphic Mutation in the TSC2 Gene J Child Neurol, March 1, 2009; 24(3): 333 - 337. [Abstract] [PDF]
|
|
|
|
 |
|
 L. S. Pymar, F. M. Platt, J. M. Askham, E. E. Morrison, and M. A. Knowles Bladder tumour-derived somatic TSC1 missense mutations cause loss of function via distinct mechanisms Hum. Mol. Genet., July 1, 2008; 17(13): 2006 - 2017. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. York, D. Lou, and D. J. Noonan Tuberin Nuclear Localization Can Be Regulated by Phosphorylation of Its Carboxyl Terminus Mol. Cancer Res., November 1, 2006; 4(11): 885 - 897. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Astrinidis, W. Senapedis, and E. P. Henske Hamartin, the tuberous sclerosis complex 1 gene product, interacts with polo-like kinase 1 in a phosphorylation-dependent manner Hum. Mol. Genet., January 15, 2006; 15(2): 287 - 297. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. J. Zacharek, Y. Xiong, and S. D. Shumway Negative Regulation of TSC1-TSC2 by Mammalian D-Type Cyclins Cancer Res., December 15, 2005; 65(24): 11354 - 11360. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Lesma, V. Grande, S. Carelli, D. Brancaccio, M. P. Canevini, R. M. Alfano, G. Coggi, A. M. Di Giulio, and A. Gorio Isolation and Growth of Smooth Muscle-Like Cells Derived from Tuberous Sclerosis Complex-2 Human Renal Angiomyolipoma: Epidermal Growth Factor Is the Required Growth Factor Am. J. Pathol., October 1, 2005; 167(4): 1093 - 1103. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Inoki, H. Ouyang, Y. Li, and K.-L. Guan Signaling by Target of Rapamycin Proteins in Cell Growth Control Microbiol. Mol. Biol. Rev., March 1, 2005; 69(1): 79 - 100. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Goncharova, D. Goncharov, D. Noonan, and V. P. Krymskaya TSC2 modulates actin cytoskeleton and focal adhesion through TSC1-binding domain and the Rac1 GTPase J. Cell Biol., December 20, 2004; 167(6): 1171 - 1182. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. J. Sales, S. Battersby, A. R. W. Williams, R. A. Anderson, and H. N. Jabbour Prostaglandin E2 Mediates Phosphorylation and Down-Regulation of the Tuberous Sclerosis-2 Tumor Suppressor (Tuberin) in Human Endometrial Adenocarcinoma Cells via the Akt Signaling Pathway J. Clin. Endocrinol. Metab., December 1, 2004; 89(12): 6112 - 6118. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Dong and D. Pan Tsc2 is not a critical target of Akt during normal Drosophila development Genes & Dev., October 15, 2004; 18(20): 2479 - 2484. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. S. Roach and S. P. Sparagana Diagnosis of Tuberous Sclerosis Complex J Child Neurol, September 1, 2004; 19(9): 643 - 649. [Abstract] [PDF]
|
|
|
|
|
|
A. Astrinidis and E. Petri Henske Aberrant Cellular Differentiation and Migration in Renal and Pulmonary Tuberous Sclerosis Complex J Child Neurol, September 1, 2004; 19(9): 710 - 715. [Abstract] [PDF]
|
|
|
|
 |
|
 O. J. Shah and T. Hunter Critical Role of T-Loop and H-Motif Phosphorylation in the Regulation of S6 Kinase 1 by the Tuberous Sclerosis Complex J. Biol. Chem., May 14, 2004; 279(20): 20816 - 20823. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K Mayer, M Goedbloed, K van Zijl, M Nellist, and H-D Rott Characterisation of a novel TSC2 missense mutation in the GAP related domain associated with minimal clinical manifestations of tuberous sclerosis J. Med. Genet., May 1, 2004; 41(5): e64 - e64. [Full Text] [PDF]
|
|
|
|
 |
|
 J. Yu, A. Astrinidis, S. Howard, and E. P. Henske Estradiol and tamoxifen stimulate LAM-associated angiomyolipoma cell growth and activate both genomic and nongenomic signaling pathways Am J Physiol Lung Cell Mol Physiol, April 1, 2004; 286(4): L694 - L700. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Astrinidis, W. Senapedis, T. R. Coleman, and E. P. Henske Cell Cycle-regulated Phosphorylation of Hamartin, the Product of the Tuberous Sclerosis Complex 1 Gene, by Cyclin-dependent Kinase 1/Cyclin B J. Biol. Chem., December 19, 2003; 278(51): 51372 - 51379. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. R. Tee, R. Anjum, and J. Blenis Inactivation of the Tuberous Sclerosis Complex-1 and -2 Gene Products Occurs by Phosphoinositide 3-Kinase/Akt-dependent and -independent Phosphorylation of Tuberin J. Biol. Chem., September 26, 2003; 278(39): 37288 - 37296. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Li, K. Inoki, P. Vacratsis, and K.-L. Guan The p38 and MK2 Kinase Cascade Phosphorylates Tuberin, the Tuberous Sclerosis 2 Gene Product, and Enhances Its Interaction with 14-3-3 J. Biol. Chem., April 11, 2003; 278(16): 13663 - 13671. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Momose, T. Kobayashi, H. Mitani, M. Hirabayashi, K. Ito, M. Ueda, Y.-i. Nabeshima, and O. Hino Identification of the coding sequences responsible for Tsc2-mediated tumor suppression using a transgenic rat system Hum. Mol. Genet., November 15, 2002; 11(24): 2997 - 3006. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Y. Liu, S. Cai, A. Espejo, M. T. Bedford, and C. L. Walker 14-3-3 Interacts with the Tumor Suppressor Tuberin at Akt Phosphorylation Site(s) Cancer Res., November 15, 2002; 62(22): 6475 - 6480. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. A. Haddad, N. Smith, M. Bowser, Y. Niida, V. Murthy, C. Gonzalez-Agosti, and V. Ramesh The TSC1 Tumor Suppressor Hamartin Interacts with Neurofilament-L and Possibly Functions as a Novel Integrator of the Neuronal Cytoskeleton J. Biol. Chem., November 8, 2002; 277(46): 44180 - 44186. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. R. Tee, D. C. Fingar, B. D. Manning, D. J. Kwiatkowski, L. C. Cantley, and J. Blenis Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling PNAS, October 15, 2002; 99(21): 13571 - 13576. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Nellist, M. A. Goedbloed, C. de Winter, B. Verhaaf, A. Jankie, A. J. J. Reuser, A. M. W. van den Ouweland, P. van der Sluijs, and D. J. J. Halley Identification and Characterization of the Interaction between Tuberin and 14-3-3zeta J. Biol. Chem., October 11, 2002; 277(42): 39417 - 39424. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. C. Dan, M. Sun, L. Yang, R. I. Feldman, X.-M. Sui, C. C. Ou, M. Nellist, R. S. Yeung, D. J. J. Halley, S. V. Nicosia, et al. Phosphatidylinositol 3-Kinase/Akt Pathway Regulates Tuberous Sclerosis Tumor Suppressor Complex by Phosphorylation of Tuberin J. Biol. Chem., September 13, 2002; 277(38): 35364 - 35370. [Abstract] [Full Text] [PDF]
|
|