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Activated Cdc42-associated Kinase 1 (Ack1) Is Required for Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL) Receptor Recruitment to Lipid Rafts and Induction of Cell Death
Wolfson Institute for Biomedical Research, University College London, WC1E 6BT London, United Kingdom.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab.
Moffitt Cancer Center, Tampa, Florida 33612, USA.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab. Wolfson Institute for Biomedical Research, University College London, WC1E 6BT London, United Kingdom.
2013 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 288, no 46, 32922-32931 p.Article in journal (Refereed) Published
Abstract [en]

TNF-related apoptosis-inducing ligand (TRAIL) holds promise for treatment of cancer due to its ability to selectively kill cancer cells while sparing normal cells. Ligand-induced translocation of TRAIL receptors (TRAIL-R) 1 and 2 (also called DR4 and DR5, respectively) into lipid raft membrane microdomains is required for TRAIL-induced cell death by facilitating receptor clustering and formation of the death-inducing signaling complex, yet the underlying regulatory mechanisms remain largely unknown. We show here that the non-receptor tyrosine kinase Ack1, previously implicated in the spatiotemporal regulation of the EGF receptor, is required for TRAIL-induced cell death in multiple epithelial cell lines. TRAIL triggered a transient up-regulation of Ack1 and its recruitment to lipid rafts along with TRAIL-R1/2. siRNA-mediated depletion of Ack1 disrupted TRAIL-induced accumulation of TRAIL-R1/2 in lipid rafts and efficient recruitment of caspase-8 to the death-inducing signaling complex. Pharmacological inhibition of Ack1 did not affect TRAIL-induced cell death, indicating that Ack1 acts in a kinase-independent manner to promote TRAIL-R1/2 accumulation in lipid rafts. These findings identify Ack1 as an essential player in the spatial regulation of TRAIL-R1/2.

Place, publisher, year, edition, pages
2013. Vol. 288, no 46, 32922-32931 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-212597DOI: 10.1074/jbc.M113.481507ISI: 000328841700010PubMedID: 24085293OAI: oai:DiVA.org:uu-212597DiVA: diva2:678474
Funder
Swedish Cancer Society, CAN 2012/581NIH (National Institute of Health), 1R01CA135328
Available from: 2013-12-12 Created: 2013-12-12 Last updated: 2017-12-06Bibliographically approved

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Pilia, GiuliaFerby, Ingvar

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