Previously, we have shown that the phosphoinositide metabolizing enzymes PIKfyve (phosphoinositide 5-kinase, FYVE finger containing) and MTMR3 (myotubularin-related protein 3), together with their lipid product PtdIns5P, are important for migration of normal human fibroblasts. As these proteins are a kinase and a phosphatase respectively, and thereby considered druggable, we wanted to test their involvement in cancer cell migration and invasion. First, we showed that PIKfyve and MTMR3 are expressed in most cancer cells. Next, we demonstrated that depletion of PIKfyve or MTMR3 resulted in decreased velocity in three different cancer cell lines by using new software for cell tracking. Inhibition of the enzymatic activity of PIKfyve by the inhibitor YM201636 also led to a strong reduction in cell velocity. Mechanistically, we show that PIKfyve and MTMR3 regulate the activation of the Rho family GTPase Rac1. Further experiments also implicated PtdIns5P in the activation of Rac1. The results suggest a model for the activation of Rac1 in cell migration where PIKfyve and MTMR3 produce PtdIns5P on cellular membranes which may then serve to recruit effectors to activate Rac1. Finally, in an invasion assay, we demonstrate that both PIKfyve and MTMR3 are implicated in invasive behaviour of cancer cells. Thus PIKfyve and MTMR3 could represent novel therapeutic targets in metastatic cancer.
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August 2014
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Research Article|
July 10 2014
PIKfyve, MTMR3 and their product PtdIns5P regulate cancer cell migration and invasion through activation of Rac1
Angela Oppelt;
Angela Oppelt
*Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, 0379 Oslo, Norway
†Department of Biochemistry, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Montebello, 0379 Oslo, Norway
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Ellen M. Haugsten;
Ellen M. Haugsten
*Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, 0379 Oslo, Norway
†Department of Biochemistry, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Montebello, 0379 Oslo, Norway
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Tobias Zech;
Tobias Zech
‡The Beatson Institute for Cancer Research, Switchback Road, Glasgow G61 1BD, U.K.
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Håvard E. Danielsen;
Håvard E. Danielsen
*Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, 0379 Oslo, Norway
§Institute for Cancer Genetics and Informatics, Oslo University Hospital, Montebello, 0379 Oslo, Norway
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Anita Sveen;
Anita Sveen
*Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, 0379 Oslo, Norway
∥Department of Cancer Prevention, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Montebello, 0379 Oslo, Norway
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Viola H. Lobert;
Viola H. Lobert
*Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, 0379 Oslo, Norway
†Department of Biochemistry, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Montebello, 0379 Oslo, Norway
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Rolf I. Skotheim;
Rolf I. Skotheim
*Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, 0379 Oslo, Norway
∥Department of Cancer Prevention, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Montebello, 0379 Oslo, Norway
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Jørgen Wesche
Jørgen Wesche
1
*Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, 0379 Oslo, Norway
†Department of Biochemistry, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Montebello, 0379 Oslo, Norway
1To whom correspondence should be addressed (email [email protected]).
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Publisher: Portland Press Ltd
Received:
January 28 2014
Revision Received:
May 13 2014
Accepted:
May 19 2014
Accepted Manuscript online:
May 19 2014
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2014 Biochemical Society
2014
Biochem J (2014) 461 (3): 383–390.
Article history
Received:
January 28 2014
Revision Received:
May 13 2014
Accepted:
May 19 2014
Accepted Manuscript online:
May 19 2014
Citation
Angela Oppelt, Ellen M. Haugsten, Tobias Zech, Håvard E. Danielsen, Anita Sveen, Viola H. Lobert, Rolf I. Skotheim, Jørgen Wesche; PIKfyve, MTMR3 and their product PtdIns5P regulate cancer cell migration and invasion through activation of Rac1. Biochem J 1 August 2014; 461 (3): 383–390. doi: https://doi.org/10.1042/BJ20140132
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