title: Manipulation of PBF/PTTG1IP phosphorylation status; a potential new therapeutic strategy for improving radioiodine uptake in thyroid and other tumors.
abstract: BACKGROUND
  The clinical effectiveness of ablative radioiodine treatment of thyroid tumors is limited by the availability of the sodium iodide symporter (NIS) at the plasma membrane (PM) for uptake of ¹³¹I. A significant proportion of well-differentiated thyroid tumors are unable to concentrate sufficient radioiodine for effective therapy, and in other tumor models such as breast tumors, where radioiodine uptake would be an attractive therapeutic option, uptake is insufficient.
  
  
  OBJECTIVE
  Pituitary tumor-transforming gene-binding factor (PBF; PTTG1IP) is overexpressed in multiple cancers and significantly decreases NIS expression at the PM. The goal of this study was to identify a method by which PBF repression of NIS may be overcome in human tumors.
  
  
  RESULTS
  Here, we identify PBF as a tyrosine phosphoprotein that specifically binds the proto-oncogene tyrosine protein kinase Src in mass spectrometry, glutathione S-transferase pulldown and coimmunoprecipitation assays. Src induction leads to phosphorylation at PBF residue Y174. Abrogation of this residue results in PM retention and a markedly reduced ability to bind NIS. The Src inhibitor PP1 inhibits PBF phosphorylation in multiple cell lines in vitro, including human primary thyroid cells. Of direct clinical importance to the treatment of thyroid cancer, PP1 stimulates iodide uptake by transfected NIS in TPC1 thyroid carcinoma cells and entirely overcomes PBF repression of iodide uptake in human primary thyroid cells.
  
  
  CONCLUSIONS
  We propose that targeting PBF phosphorylation at residue Y174 via tyrosine kinase inhibitors may be a novel therapeutic strategy to enhance the efficacy of ablative radioiodine treatment in thyroid and other endocrine and endocrine-related tumors.
authors.affiliation: School of Clinical and Experimental Medicine, Institute of Biomedical Research, University of Birmingham, Birmingham B15 2TT, United Kingdom.
authors.forename: V E
authors.initials: VE
authors.lastname: Smith
authors.forename: N
authors.initials: N
authors.lastname: Sharma
authors.forename: R J
authors.initials: RJ
authors.lastname: Watkins
authors.forename: M L
authors.initials: ML
authors.lastname: Read
authors.forename: G A
authors.initials: GA
authors.lastname: Ryan
authors.forename: P P
authors.initials: PP
authors.lastname: Kwan
authors.forename: A
authors.initials: A
authors.lastname: Martin
authors.forename: J C
authors.initials: JC
authors.lastname: Watkinson
authors.forename: K
authors.initials: K
authors.lastname: Boelaert
authors.forename: J A
authors.initials: JA
authors.lastname: Franklyn
authors.forename: C J
authors.initials: CJ
authors.lastname: McCabe
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D019556:COS Cells; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007457:Iodine Radioisotopes / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D050505:Mutant Proteins / Q000378:metabolism; D009363:Neoplasm Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D000090063:Proto-Oncogene Mas; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000037:antagonists & inhibitors / Q000378:metabolism; D019275:Radiopharmaceuticals / Q000378:metabolism; D011994:Recombinant Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D027981:Symporters / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D013961:Thyroid Gland / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D013964:Thyroid Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy; D000099209:Sodium-Iodide Symporters
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D007457:Iodine Radioisotopes; D008565:Membrane Proteins; D050505:Mutant Proteins; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D000090063:Proto-Oncogene Mas; D016392:Proto-Oncogene Proteins pp60(c-src); D019275:Radiopharmaceuticals; D011994:Recombinant Proteins; D027981:Symporters; D000099209:Sodium-Iodide Symporters; C000715470:MAS1 protein, human; C112633:PTTG1IP protein, human