title: HIF-1α-independent hypoxia-induced rapid PTK6 stabilization is associated with increased motility and invasion.
abstract: PTK6/Brk is a non-receptor tyrosine kinase overexpressed in cancer. Here we demonstrate that cytosolic PTK6 is rapidly and robustly induced in response to hypoxic conditions in a HIF-1-independent manner. Furthermore, a proportion of hypoxic PTK6 subsequently re-localized to the cell membrane. We observed that the rapid stabilization of PTK6 is associated with a decrease in PTK6 ubiquitylation and we have identified c-Cbl as a putative PTK6 E3 ligase in normoxia. The consequences of hypoxia-induced PTK6 stabilization and subcellular re-localization to the plasma membrane include increased cell motility and invasion, suggesting PTK6 targeting as a therapeutic approach to reduce hypoxia-regulated metastatic potential. This could have particular significance for breast cancer patients with triple negative disease.
authors.affiliation: CR-UK/MRC Oxford Institute for Radiation Oncology; Department of Oncology; University of Oxford; Oxford, UK; School of Biological, Biomedical and Environmental Sciences; University of Hull; Hull, UK.
authors.forename: Isabel M
authors.initials: IM
authors.lastname: Pires
authors.affiliation: CR-UK/MRC Oxford Institute for Radiation Oncology; Department of Oncology; University of Oxford; Oxford, UK.
authors.forename: Nina Jg
authors.initials: NJ
authors.lastname: Blokland
authors.affiliation: CR-UK/MRC Oxford Institute for Radiation Oncology; Department of Oncology; University of Oxford; Oxford, UK.
authors.forename: Agnieke Wt
authors.initials: AW
authors.lastname: Broos
authors.affiliation: School of Biological, Biomedical and Environmental Sciences; University of Hull; Hull, UK.
authors.forename: Flore-Anne
authors.initials: FA
authors.lastname: Poujade
authors.affiliation: CR-UK/MRC Oxford Institute for Radiation Oncology; Department of Oncology; University of Oxford; Oxford, UK.
authors.forename: Joana M
authors.initials: JM
authors.lastname: Senra
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit; The Institute of Cancer Research; Sutton, UK.
authors.forename: Suzanne A
authors.initials: SA
authors.lastname: Eccles
authors.affiliation: Radboud University Nijmegen Medical Centre; Radiation Oncology; Nijmegen, the Netherlands.
authors.forename: Paul N
authors.initials: PN
authors.lastname: Span
authors.affiliation: Biosciences; Brunel Institute for Cancer Genetics and Pharmacogenomics; Brunel University; Uxbridge, UK.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Harvey
authors.affiliation: CR-UK/MRC Oxford Institute for Radiation Oncology; Department of Oncology; University of Oxford; Oxford, UK.
authors.forename: Ester M
authors.initials: EM
authors.lastname: Hammond
mesh_terms: D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002465:Cell Movement; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000473:pathology; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D050721:Proto-Oncogene Proteins c-cbl / Q000378:metabolism; D064726:Triple Negative Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D054875:Ubiquitination
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009363:Neoplasm Proteins; D050721:Proto-Oncogene Proteins c-cbl; D011505:Protein-Tyrosine Kinases; C088375:PTK6 protein, human; C067419:CBL protein, human; D010100:Oxygen
keywords: Brk; PTK6; hypoxia; invasion; metastasis; migration; ubiquitylation