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Cancer Biol Ther. 2014 Oct;15(10):1350-7. doi: 10.4161/cbt.29822. Epub 2014 Jul 14.

HIF-1α-independent hypoxia-induced rapid PTK6 stabilization is associated with increased motility and invasion.

Author information

  • 1CR-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.
  • 2CR-UK/MRC Oxford Institute for Radiation Oncology; Department of Oncology; University of Oxford; Oxford, UK.
  • 3School of Biological, Biomedical and Environmental Sciences; University of Hull; Hull, UK.
  • 4Cancer Research UK Cancer Therapeutics Unit; The Institute of Cancer Research; Sutton, UK.
  • 5Radboud University Nijmegen Medical Centre; Radiation Oncology; Nijmegen, the Netherlands.
  • 6Biosciences; Brunel Institute for Cancer Genetics and Pharmacogenomics; Brunel University; Uxbridge, UK.

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.

KEYWORDS:

Brk; PTK6; hypoxia; invasion; metastasis; migration; ubiquitylation

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