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HIF-1?-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.

SUBMITTER: Pires IM

PROVIDER: S-EPMC4130728 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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

Pires Isabel M IM Blokland Nina Jg NJ Broos Agnieke Wt AW Poujade Flore-Anne FA Senra Joana M JM Eccles Suzanne A SA Span Paul N PN Harvey Amanda J AJ Hammond Ester M EM

Cancer biology & therapy 20140714 10

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-indu ...[more]

PMID: 25019382

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