title: PTEN lipid phosphatase activity and proper subcellular localization are necessary and sufficient for down-regulating AKT phosphorylation in the nucleus in Cowden syndrome.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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 suppresses nuclear 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.
authors.affiliation: Cleveland Clinic, 9500 Euclid Avenue, NE50, Cleveland, Ohio 44195, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: He
authors.forename: Motoyasu
authors.initials: M
authors.lastname: Saji
authors.forename: Deepa
authors.initials: D
authors.lastname: Radhakrishnan
authors.forename: Todd
authors.initials: T
authors.lastname: Romigh
authors.forename: Joanne
authors.initials: J
authors.lastname: Ngeow
authors.forename: Qi
authors.initials: Q
authors.lastname: Yu
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Ringel
authors.forename: Charis
authors.initials: C
authors.lastname: Eng
mesh_terms: D000236:Adenoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000328:Adult; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003593:Cytoplasm / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation; D006223:Hamartoma Syndrome, Multiple / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D013964:Thyroid Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase