+ Site Statistics
References:
54,258,434
Abstracts:
29,560,870
PMIDs:
28,072,757
+ Search Articles
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ PDF Full Text
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Translate
+ Recently Requested

Hamartin, the tuberous sclerosis complex 1 gene product, interacts with polo-like kinase 1 in a phosphorylation-dependent manner



Hamartin, the tuberous sclerosis complex 1 gene product, interacts with polo-like kinase 1 in a phosphorylation-dependent manner



Human Molecular Genetics 15(2): 287-297



Tuberous sclerosis complex (TSC) 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 G(2)/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 N-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, whereas 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 (MEFs) 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.

(PDF emailed within 0-6 h: $19.90)

Accession: 012138624

Download citation: RISBibTeXText

PMID: 16339216

DOI: 10.1093/hmg/ddi444


Related references

Cell cycle-regulated phosphorylation of hamartin, the product of the tuberous sclerosis complex 1 gene, by cyclin-dependent kinase 1/cyclin B. Journal of Biological Chemistry 278(51): 51372-9, 2003

Hamartin, the product of the tuberous sclerosis 1 gene, interacts with tuberin and appears to be localized to cytoplasmic vesicles. Cancer Research 58(21): 4766-4770, Nov 1, 1998

Hamartin, the product of the tuberous sclerosis 1 (TSC1) gene, interacts with tuberin and appears to be localized to cytoplasmic vesicles. Cancer Research 58(21): 4766-4770, 1998

The tuberous sclerosis 2 gene product can localize to nuclei in a phosphorylation-dependent manner. Molecular Cell Biology Research Communications 4(6): 374-380, 2001

Dissociate expression of tuberous sclerosis complex 1 product hamartin in a skin and pulmonary lesion of a tuberous sclerosis complex. Human Pathology 40(3): 430-434, 2008

Inactivation of the tuberous sclerosis complex-1 and -2 gene products occurs by phosphoinositide 3-kinase/Akt-dependent and -independent phosphorylation of tuberin. Journal of Biological Chemistry 278(39): 37288-37296, 2003

Cellular and subcellular expression of Hamartin, the product of the Tuberous Sclerosis 1 gene. Journal of the American Society of Nephrology 9(PROGRAM AND ABSTR ISSUE): 445A, Sept, 1998

Rheb binds tuberous sclerosis complex 2 (TSC2) and promotes S6 kinase activation in a rapamycin- and farnesylation-dependent manner. Journal of Biological Chemistry 278(35): 32493-6, 2003

Tuberous sclerosis complex 2 gene product interacts with human SMAD proteins. A molecular link of two tumor suppressor pathways. Journal of Biological Chemistry 279(24): 25605-25613, 2004

Reduction of expression of tuberin, the tuberous-sclerosis-complex-gene-2 product in tuberous sclerosis complex associated connective tissue nevi and sporadic squamous and basal cell carcinomas. Journal of Cutaneous Pathology 29(5): 287-290, 2002

Tuberous Sclerosis Complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb. Current Biology 13(15): 1259-1268, August 5, 2003

The Drosophila modifier of variegation modulo gene product binds specific RNA sequences at the nucleolus and interacts with DNA and chromatin in a phosphorylation-dependent manner. Journal of Biological Chemistry 274(10): 6315-6323, 1999

Expression of the tuberous sclerosis complex gene products, hamartin and tuberin, in central nervous system tissues. Acta Neuropathologica 99(3): 223-230, March, 2000

Identification of the tuberous sclerosis complex-2 gene product tuberin as a target of the phosphoinositide 3-kinase/Akt pathway. Molecular Biology of the Cell 13(Supplement): 293a, 2002