Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
ACK1 is a mechanoresponsive kinase required for SCF (β-TrCP)-mediated degradation of YAP/TAZ
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Ludwig Institute for Cancer Research, Uppsala Sweden.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Ludwig Institute for Cancer Research, Uppsala Sweden.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Ludwig Institute for Cancer Research, Uppsala Sweden.
(English)Manuscript (preprint) (Other academic)
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-349179OAI: oai:DiVA.org:uu-349179DiVA, id: diva2:1199894
Available from: 2018-04-23 Created: 2018-04-23 Last updated: 2018-10-23
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: 2018-09-27

Open Access in DiVA

No full text in DiVA

Search in DiVA

By author/editor
Pilia, Giulia
By organisation
Department of Medical Biochemistry and Microbiology
Cell and Molecular Biology

Search outside of DiVA

GoogleGoogle Scholar

urn-nbn

Altmetric score

urn-nbn
Total: 75 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf