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Human Molecular Genetics Advance Access published online on December 8, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi444
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© The Author 2005. Published by Oxford University Press. All rights reserved
Received September 28, 2005
Revised November 30, 2005
Accepted November 30, 2005

Article

Hamartin, the Tuberous Sclerosis Complex 1 (TSC1) gene product, interacts with Polo-like kinase 1 (PLK1) in a phosphorylation-dependent manner

Aristotelis Astrinidis 1, William Senapedis 1, and Elizabeth P. Henske 2 *

1 Fox Chase Cancer Center, Philadelphia, PA 19111, USA
2 Fox Chase Cancer Center, 333 Cottman Ave., Philadelphia PA 19111, USA

* To whom correspondence should be addressed.
Elizabeth P. Henske, E-mail: Elizabeth.Henske{at}fccc.edu


  Abstract

Tuberous sclerosis complex is a tumor suppressor gene syndrome caused by mutations in TSC1 and TSC2. Hamartin and tuberin, the products of TSC1 and TSC2, respectively, form heterodimers and inhibit the mammalian target of rapamycin. Previously, we have shown that hamartin is phosphorylated by CDC2/cyclin B1 during the G2/M phase of the cell cycle. Here we report that hamartin is localized to the centrosome and that phosphorylated hamartin and phosphorylated tuberin co-immunoprecipitate with the mitotic kinase Plk1. Plk1 interacts with the NH2-terminus of hamartin (amino acids 1-880), which contains two potential Plk1 binding sites (T310 and S332). Phosphorylated hamartin interacts with Plk1 independent of tuberin with all three proteins present in a complex. A non-phosphorylatable hamartin mutant with an alanine substitution at residue T310 does not interact with Plk1, while a non-phosphorylatable hamartin mutant at residue S332 in conjunction with alanine mutations at the other CDC2/cyclin B1 sites (T417, S584, and T1047) does not impact hamartin binding to Plk1. Hamartin negatively regulates the protein levels of Plk1. Finally, Tsc1-/- mouse embryonic fibroblasts have increased number of centrosomes and increased DNA content, compared to Tsc1+/+ cells. Both phenotypes are rescued after pre-treatment with the mTOR inhibitor rapamycin. RNAi inhibition of Plk1 in Tsc1-/- MEFs failed to rescue the increased centrosome number phenotype. These data reveal a novel subcellular localization for hamartin and a novel interaction partner for the hamartin/tuberin complex, and implicate hamartin and mTOR in the regulation of centrosome duplication.


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