title: PTK6 regulates IGF-1-induced anchorage-independent survival.
abstract: BACKGROUND
  Proteins that are required for anchorage-independent survival of tumor cells represent attractive targets for therapeutic intervention since this property is believed to be critical for survival of tumor cells displaced from their natural niches. Anchorage-independent survival is induced by growth factor receptor hyperactivation in many cell types. We aimed to identify molecules that critically regulate IGF-1-induced anchorage-independent survival.
  
  
  RESULTS
  We conducted a high-throughput siRNA screen and identified PTK6 as a critical component of IGF-1 receptor (IGF-1R)-induced anchorage-independent survival of mammary epithelial cells. PTK6 downregulation induces apoptosis of breast and ovarian cancer cells deprived of matrix attachment, whereas its overexpression enhances survival. Reverse-phase protein arrays and subsequent analyses revealed that PTK6 forms a complex with IGF-1R and the adaptor protein IRS-1, and modulates anchorage-independent survival by regulating IGF-1R expression and phosphorylation. PTK6 is highly expressed not only in the previously reported Her2(+) breast cancer subtype, but also in high grade ER(+), Luminal B tumors and high expression is associated with adverse outcomes.
  
  
  CONCLUSIONS
  These findings highlight PTK6 as a critical regulator of anchorage-independent survival of breast and ovarian tumor cells via modulation of IGF-1 receptor signaling, thus supporting PTK6 as a potential therapeutic target for multiple tumor types. The combined genomic and proteomic approaches in this report provide an effective strategy for identifying oncogenes and their mechanism of action.
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Hanna Y
authors.initials: HY
authors.lastname: Irie
authors.forename: Yashaswi
authors.initials: Y
authors.lastname: Shrestha
authors.forename: Laura M
authors.initials: LM
authors.lastname: Selfors
authors.forename: Fabianne
authors.initials: F
authors.lastname: Frye
authors.forename: Naoko
authors.initials: N
authors.lastname: Iida
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Wang
authors.forename: Lihua
authors.initials: L
authors.lastname: Zou
authors.forename: Jun
authors.initials: J
authors.lastname: Yao
authors.forename: Yiling
authors.initials: Y
authors.lastname: Lu
authors.forename: Charles B
authors.initials: CB
authors.lastname: Epstein
authors.forename: Sridaran
authors.initials: S
authors.lastname: Natesan
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Richardson
authors.forename: Kornelia
authors.initials: K
authors.lastname: Polyak
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.forename: William C
authors.initials: WC
authors.lastname: Hahn
authors.forename: Joan S
authors.initials: JS
authors.lastname: Brugge
mesh_terms: D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005455:Fluorescent Antibody Technique; D006801:Humans; D047468:Immunoprecipitation; D017404:In Situ Hybridization, Fluorescence; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism* / Q000494:pharmacology; D053208:Kaplan-Meier Estimate; D018613:Microscopy, Confocal; D008858:Microscopy, Phase-Contrast; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism
chemical_list: C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D009363:Neoplasm Proteins; D007334:Insulin-Like Growth Factor I; D011505:Protein-Tyrosine Kinases; D017526:Receptor, IGF Type 1; C088375:PTK6 protein, human