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  • 1.
    Hopkins, Sarah
    et al.
    Wolfson Institute for Biomedical Research, University College London, Gower Street, London WC1E 6BT, UK.
    Linderoth, Emma
    Wolfson Institute for Biomedical Research, University College London, Gower Street, London WC1E 6BT, UK.
    Hantschel, Oliver
    CeMM – Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, 1090 Vienna, Austria.
    Suarez-Henriques, Paula
    Wolfson Institute for Biomedical Research, University College London, Gower Street, London WC1E 6BT, UK.
    Pilia, Giulia
    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.
    Kendrick, Howard
    Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
    Smalley, Matthew J
    Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
    Superti-Furga, Giulio
    CeMM – Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, 1090 Vienna, Austria.
    Ferby, Ingvar
    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.
    Mig6 Is a Sensor of EGF Receptor Inactivation that Directly Activates c-Abl to Induce Apoptosis during Epithelial Homeostasis.2012In: Developmental Cell, ISSN 1534-5807, E-ISSN 1878-1551, Vol. 23, no 3, p. 547-559Article in journal (Refereed)
    Abstract [en]

    A fundamental aspect of epithelial homeostasis is the dependence on specific growth factors for cell survival, yet the underlying mechanisms remain obscure. We found an "inverse" mode of receptor tyrosine kinase signaling that directly links ErbB receptor inactivation to the induction of apoptosis. Upon ligand deprivation Mig6 dissociates from the ErbB receptor and binds to and activates the tyrosine kinase c-Abl to trigger p73-dependent apoptosis in mammary epithelial cells. Deletion of Errfi1 (encoding Mig6) and inhibition or RNAi silencing of c-Abl causes impaired apoptosis and luminal filling of mammary ducts. Mig6 activates c-Abl by binding to the kinase domain, which is prevented in the presence of epidermal growth factor (EGF) by Src family kinase-mediated phosphorylation on c-Abl-Tyr488. These results reveal a receptor-proximal switch mechanism by which Mig6 actively senses EGF deprivation to directly activate proapoptotic c-Abl. Our findings challenge the common belief that deprivation of growth factors induces apoptosis passively by lack of mitogenic signaling.

  • 2.
    Linderoth, Emma
    et al.
    Wolfson Institute for Biomedical Research, University College London, WC1E 6BT London, United Kingdom.
    Pilia, Giulia
    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.
    Mahajan, Nupam P
    Moffitt Cancer Center, Tampa, Florida 33612, USA.
    Ferby, Ingvar
    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.
    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 Death2013In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 288, no 46, p. 32922-32931Article in journal (Refereed)
    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.

  • 3.
    Pilia, Giulia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Ludwig Institute for Cancer Research, Uppsala.
    Novel Roles of the Ack1 Kinase in Epithelial Biology2018Doctoral 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.

    List of papers
    1. 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
    Open this publication in new window or tab >>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
    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.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-212597 (URN)10.1074/jbc.M113.481507 (DOI)000328841700010 ()24085293 (PubMedID)
    Funder
    Swedish Cancer Society, CAN 2012/581NIH (National Institute of Health), 1R01CA135328
    Available from: 2013-12-12 Created: 2013-12-12 Last updated: 2018-04-26Bibliographically approved
    2. ACK1 is a mechanoresponsive kinase required for SCF (β-TrCP)-mediated degradation of YAP/TAZ
    Open this publication in new window or tab >>ACK1 is a mechanoresponsive kinase required for SCF (β-TrCP)-mediated degradation of YAP/TAZ
    (English)Manuscript (preprint) (Other academic)
    National Category
    Cell and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-349179 (URN)
    Available from: 2018-04-23 Created: 2018-04-23 Last updated: 2018-04-26
    3. Ack1 is a negative regulator of ErbB3 that acts both by promoting its degradation and suppressing its expression
    Open this publication in new window or tab >>Ack1 is a negative regulator of ErbB3 that acts both by promoting its degradation and suppressing its expression
    (English)Manuscript (preprint) (Other academic)
    National Category
    Cell and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-349182 (URN)
    Available from: 2018-04-23 Created: 2018-04-23 Last updated: 2018-04-26
1 - 3 of 3
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