PTEN Lipid Phosphatase Activity and Proper Subcellular Localization Are Necessary and Sufficient for Down-Regulating AKT Phosphorylation in the Nucleus in Cowden Syndrome

Divisions of Endocrinology, Diabetes, and Metabolism and Oncology (M.S., M.D.R.), Department of Internal Medicine, and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210
The Journal of Clinical Endocrinology and Metabolism (Impact Factor: 6.21). 09/2012; 97(11). DOI: 10.1210/jc.2012-1991
Source: PubMed


Context:Germline mutations in PTEN are associated with phosphatase and tensin homolog deleted on chromosome 10 (PTEN) hamartoma tumor syndrome including Cowden syndrome (CS) and Cowden-like syndrome (CSL) that predisposes to high risks of benign and malignant tumors of thyroid and breast.Objective:The objective of the study was to analyze the subcellular pattern of phosphorylated (P)-AKT expression in nonmedullary thyroid cancers from PTEN hamartoma tumor syndrome patients and to investigate whether the lack of PTEN in the nucleus and/or lack of proper PTEN function in the nucleus affect(s) nuclear AKT activity in CS patients.Design:In all, 664 patients with CS/CSL were screened for PTEN germline mutations and nonmedullary thyroid cancers. Twenty-two patients who have both pathogenic PTEN germline mutations and nonmedullary thyroid cancers were selected. Thyroid samples from these patients were stained for PTEN and P-AKT. In our in vitro study, PTEN was knocked down or overexpressed in both thyroid cancer cells and breast cancer cells, and nuclear P-AKT was compared with the control.Results:Loss of PTEN protein was found in thyroid adenomas and carcinomas from all 22 (100%) PTEN(Mut+) CS/CSL patients. AKT activation was identified in 17 of 22 (77.3%) thyroid adenoma/carcinoma specimens, and most patients (63.7%) have activated nuclear AKT. Knockdown of PTEN in cells containing wild-type PTEN enhanced nuclear P-AKT, whereas expression of wild-type PTEN, but not phosphatase-dead mutants (C124S or G129E), markedly reduced nuclear P-AKT in PTEN null cells. We also showed that in breast cancer but not thyroid cancer cells, PTEN suppressesnuclear P-AKT mainly through decreasing P-AKT nuclear translocation by reducing the PIP3/P-AKT reservoir in the cytoplasm. In thyroid cancer cells, PTEN suppresses phosphorylation of AKT already resident in the nucleus.Conclusions:PTEN is necessary and sufficient for inhibiting AKT activation in the nucleus through its intact lipid phosphatase activity and proper subcellular localization.

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    • "PTEN is regulated transcriptionally, post-transcriptionally and through epigenetic silencing via promoter methylation yet research on post-translational modulations of PTEN has attracted much attention in recent years. A number of PTEN functions have been attributed to its ability to traverse through different sub-cellular locations [17] [18] [19]. Several mechanisms for the nucleo-cytoplasmic shuttling of PTEN have been outlined till date. "
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    ABSTRACT: PTEN (Phosphatase and Tensin Homolog deleted on Chromosome TEN), the tumor suppressor is the regulator-in-chief of a variety of cellular processes that include cell proliferation, growth, migration and death. Since its identification, numerous reports of PTEN loss or mutation in multiple cancer types has rendered this gene to be one of the most frequently affected tumor suppressors of the post p53 era. With the ever increasing number of processes under PTEN surveillance, the master regulator itself should be under strict control. Although PTEN can be regulated at the genetic and epigenetic levels, post-translational modulations emerge as the focal point of regulation. Here, we will outline the key regulatory aspects of PTEN with an emphasis on the post-translational front. Exciting new evidences will be put forth for the sub-cellular trafficking of PTEN that regulates its functioning with a focus on ubiquitination, phosphorylation and sumoylation. The ability of PTEN to form protein scaffold structures has been overviewed from the aspect of novel regulatory mechanism. The probable contribution of these regulatory mechanisms in suppression or elevation of the tumor suppressive role of PTEN will be discussed. The role of the carboxyl terminus of PTEN in combating its negative regulators will be analyzed as a potential therapeutic approach. Overall, these under-rated, emerging modes of PTEN modulations significantly re-focus the established notion of PTEN regulation and might be targeted in unraveling novel cancer therapeutics.
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    ABSTRACT: Reversible tyrosine phosphorylation of proteins is a key regulatory mechanism to steer normal development and physiological functioning of multicellular organisms. Phosphotyrosine dephosphorylation is exerted by members of the super-family of protein tyrosine phosphatase (PTP) enzymes and many play such essential roles that a wide variety of hereditary disorders and disease susceptibilities in man are caused by PTP alleles. More than two decades of PTP research has resulted in a collection of PTP genetic variants with corresponding consequences at the molecular, cellular and physiological level. Here we present a comprehensive overview of these PTP gene variants that have been linked to disease states in man. Although the findings have direct bearing for disease diagnostics and for research on disease etiology, more work is necessary to translate this into therapies that alleviate the burden of these hereditary disorders and disease susceptibilities in man.
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