Role of DARPP-32 in Breast Cancer Cell Signalling and Migration
Author
Summary, in English
This thesis describes the identification of DARPP-32 as a novel interactionpartner to DDR1. We demonstrate that DARPP-32 inhibits MCF-7 cell migration and that this effect requires phosphorylation of threonine-34, an event catalyzed by protein kinase A (PKA) and strongly induced by detachment of cells from the culture substrate. DARPP-32 mediated inhibition of migration proved to be dependent on DDR1 expression consolidating a functional relevance of the interaction between DARPP-32 and DDR1. In addition, we found that Wnt-5a could directly trigger a cAMP response that resulted in phosphorylation of DARPP-32 and stimulation with Wnt-5a was nessecary for DARPP-32 mediated inhibition of cell migration in wound healing assay.
The anti-migratory effects of Wnt-5a and DARPP-32 were reduced by dominant negative CREB, which suggests that CREB plays a functional role in this signalling mechanism. Finally, we found that phospho-DARPP-32 inhibited the activity of the focal adhesion kinase (FAK) in MCF-7 breast cancer cells, and that MCF-7 cells expressing phospho-DARPP-32 displayed less filopodia formation. These results suggest that DARPP-32 restricts the migration of breast epithelial cells via both a transcription dependent mechanism that involves CREB and a transcription independent mechanism affecting FAK. Pharmacological activation of this pathway may constitute a novel way of limiting breast cancer metastasis.
Department/s
- Molecular Neurobiology
- Experimental Pathology, Malmö
Publishing year
2008
Language
English
Publication/Series
Faculty of Medicine Doctoral Dissertation Series
Volume
2008:3
Full text
- Available as PDF - 11 MB
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Document type
Dissertation
Publisher
Experimental Pathology
Topic
- Cancer and Oncology
Keywords
- cell migration
- protein phosphatase 1.
- DARPP-32
- breast cancer
- protein kinase A
Status
Published
Research group
- Molecular Neurobiology
- Experimental Pathology, Malmö
Supervisor
ISBN/ISSN/Other
- ISSN: 1652-8220
- ISBN: 978-91-85897-59-9
Defence date
25 January 2008
Defence time
09:15
Defence place
Main lecture hall, Pathology Building, Entrance 78, U-MAS, Malmö
Opponent
- Per Svenningsson (Dr.)