Year-end Sale % OFF 
Abstract
BackgroundIntegrins and enzymes of the eicosanoid pathway are both well-established contributors to cancer. However, this is the first report of the interdependence of the two signaling systems. In a screen for proteins that interacted with, and thereby potentially regulated, the human platelet-type 12-lipoxygenase (12-LOX, ALOX12), we identified the integrin β4 (ITGB4).MethodsUsing a cultured mammalian cell model, we have demonstrated that ITGB4 stimulation leads to recruitment of 12-LOX from the cytosol to the membrane where it physically interacts with the integrin to become enzymatically active to produce 12(S)-HETE, a known bioactive lipid metabolite that regulates numerous cancer phenotypes.ResultsThe net effect of the interaction was the prevention of cell death in response to starvation. Additionally, regulation of β4-mediated, EGF-stimulated invasion was shown to be dependent on 12-LOX, and downstream Erk signaling in response to ITGB4 activation also required 12-LOX.ConclusionsThis is the first report of an enzyme of the eicosanoid pathway being recruited to and regulated by activated β4 integrin. Integrin β4 has recently been shown to induce expansion of prostate tumor progenitors and there is a strong correlation between stage/grade of prostate cancer and 12-LOX expression. The 12-LOX enzymatic product, 12(S)-HETE, regulates angiogenesis and cell migration in many cancer types. Therefore, disruption of integrin β4-12LOX interaction could reduce the pro-inflammatory oncogenic activity of 12-LOX. This report on the consequences of 12-LOX and ITGB4 interaction sets a precedent for the linkage of integrin and eicosanoid biology through direct protein-protein association.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-015-0382-5) contains supplementary material, which is available to authorized users.
Highlights
Integrins and enzymes of the eicosanoid pathway are both well-established contributors to cancer
Cells were stimulated with an antibody to the extracellular domain of β4 subunit (3E1), and β4-associated proteins were subsequently immunoprecipitated from extracts using antibodies that either recognized the extracellular domain (3E1, 439-9B) or the cytoplasmic domain of β4 (450-11A), and these were probed for the presence of 12-LOX
These data suggest that the interaction between 12-LOX and β4 originally discovered in the yeast 2-hybrid model system occurs in a cultured human tumor cell model
Summary
Integrins and enzymes of the eicosanoid pathway are both well-established contributors to cancer. This is the first report of the interdependence of the two signaling systems. In a screen for proteins that interacted with, and thereby potentially regulated, the human platelet-type 12-lipoxygenase (12-LOX, ALOX12), we identified the integrin β4 (ITGB4). The human β4 integrin subunit was identified as a 12-LOXinteracting protein, and a potential 12-LOX regulator [1]. The β4 integrin subunit is part of a cell surface receptor (α6β4) for laminin (LN), an extracellular matrix component Ligation of this surface receptor by LN or by an activating antibody (3E1), triggers signaling pathways involved in cell proliferation, differentiation, apoptosis, adhesion, invasion and metastasis [2]. The platelet-type 12-LOX (P-12-LOX) is one of three mammalian 12-LOX isoforms (classified as platelet-, leukocyte-, or epidermal-type) that differ in tissue
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
