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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, p. 32922-32931Article 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, p. 32922-32931
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, id: diva2:678474
Funder
Swedish Cancer Society, CAN 2012/581NIH (National Institute of Health), 1R01CA135328Available from: 2013-12-12 Created: 2013-12-12 Last updated: 2018-04-26Bibliographically approved
In thesis
1. Novel Roles of the Ack1 Kinase in Epithelial Biology
Open this publication in new window or tab >>Novel Roles of the Ack1 Kinase in Epithelial Biology
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Epithelial homeostasis is maintained through integration of diverse signals that regulate cell fate. A strict control of such signals is required to prevent overproliferation and, ultimately, oncogenesis. In this thesis we identify novel roles of Activated Cdc42-associated kinase 1 (Ack1) in maintenance of epithelial homeostasis. Ack1 has been previously linked to cytoskeletal remodeling, signal transduction and gene expression regulation. Interestingly, our work reveals that Ack1 is also important for I) promoting extrinsic apoptosis, II) mediating mechanically-induced inhibition of proliferation and III) attenuating mitogenic signals, fundamental functions to prevent aberrant tissue growth.

Apoptosis is a program of regulated cell death that can be triggered by several pathways. Among them, the TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis cascade has raised interest for cancer treatment, as many cancer cell lines are susceptible to it. We found that Ack1 increases sensitivity to TRAIL by promoting translocation of ligand-bound TRAIL-Receptor to lipid rafts. Localisation at the lipid rafts, in turn, favors recruitment of downstream signalling effectors, enhancing the apoptotic response.

Yap and Taz are transcriptional co-factors that integrate mechanical and soluble cues to regulate cell proliferation and differentiation. Yap/Taz regulation is mediated by cytoplasmic sequestration and, particularly for Taz, proteasomal degradation via ubiquitination by the E3 ligase β-TrCP. We discovered that Ack1 is activated by mechanical signals and promotes nuclear exclusion of Yap/Taz. Ack1 promotes Yap/Taz interaction with β-TRCP and it is required for efficient degradation of Taz. Consequently, Ack1 limits Yap/Taz-dependent gene expression and cell proliferation.

The ErbB family of receptor tyrosine kinases mediates pro-survival and proliferative signals of crucial importance in development and cancer. Among the ErbB family members, ErbB3 has significant oncogenic properties as it potently activates the PI3K/Akt signaling pathway. We observe that Ack1 depletion increases ErbB3 total levels, but not EGFR and ErbB2, and is required for both basal turnover of ErbB3 and its ligand-induced degradation. Consequently, Ack1 attenuates ErbB3-dependent signalling upon Neuregulin-1β treatment. Additionally, Ack1 reduces ErbB3 gene expression both at steady state and upon stimulation, revealing its importance as multi-level regulator of ErbB3.

Taken together, our data depict new roles for Ack1 in epithelial cells, highlighting its multifaceted role in maintenance of epithelial homeostasis.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 85
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1469
Keywords
Ack1, Epithelial homeostasis, Cell Signalling, Cancer, Apoptosis, TRAIL-R, Yap/Taz, Mechanotransduction, ErbB3
National Category
Cell and Molecular Biology
Research subject
Molecular Cellbiology
Identifiers
urn:nbn:se:uu:diva-349384 (URN)978-91-513-0355-0 (ISBN)
Public defence
2018-08-21, B42, BMC, Husargatan 3, Uppsala, 13:00 (English)
Opponent
Supervisors
Available from: 2018-05-30 Created: 2018-04-26 Last updated: 2018-05-30

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Pilia, GiuliaFerby, Ingvar

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