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Eur J Cell Biol. 2019 Dec;98(5-8):151046. doi: 10.1016/j.ejcb.2019.151046. Epub 2019 Oct 11.

CRN2 binds to TIMP4 and MMP14 and promotes perivascular invasion of glioblastoma cells.

Author information

1
Centre for Biochemistry, Institute of Biochemistry I, Medical Faculty, University of Cologne, 50931, Cologne, Germany.
2
In-vivo NMR, Max Planck Institute for Metabolism Research, 50931, Cologne, Germany.
3
Centre for Biochemistry, Institute of Biochemistry I, Medical Faculty, University of Cologne, 50931, Cologne, Germany; Institute of Aerospace Medicine, German Aerospace Center (DLR), 51147, Cologne, Germany.
4
German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Centre Munich, German Research Centre for Environmental Health, 85764, Neuherberg, Germany.
5
German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Centre Munich, German Research Centre for Environmental Health, 85764, Neuherberg, Germany; Institute of Developmental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764, Neuherberg, Germany.
6
German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Centre Munich, German Research Centre for Environmental Health, 85764, Neuherberg, Germany; Chair of Experimental Genetics, School of Life Science Weihenstephan, Technische Universität München, 85354, Freising, Germany; German Center for Diabetes Research (DZD), 85764, Neuherberg, Germany.
7
Comparative Medicine, Center for Molecular Medicine Cologne, University of Cologne, 50931, Cologne, Germany.
8
Institute of Neuropathology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, 91054, Erlangen, Germany.
9
Medizinisches Proteom‑Center, Medical Faculty, Ruhr-University Bochum, 44801, Bochum, Germany.
10
Centre for Biochemistry, Institute of Biochemistry I, Medical Faculty, University of Cologne, 50931, Cologne, Germany. Electronic address: noegel@uni-koeln.de.
11
Centre for Biochemistry, Institute of Biochemistry I, Medical Faculty, University of Cologne, 50931, Cologne, Germany; Institute of Neuropathology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, 91054, Erlangen, Germany; Center for Physiology and Pathophysiology, Institute of Vegetative Physiology, Medical Faculty, University of Cologne, 50931, Cologne, Germany. Electronic address: christoph.clemen@uni-koeln.de.

Abstract

CRN2 is an actin filament binding protein involved in the regulation of various cellular processes including cell migration and invasion. CRN2 has been implicated in the malignant progression of different types of human cancer. We used CRN2 knock-out mice for analyses as well as for crossbreeding with a Tp53/Pten knock-out glioblastoma mouse model. CRN2 knock-out mice were subjected to a phenotyping screen at the German Mouse Clinic. Murine glioblastoma tissue specimens as well as cultured murine brain slices and glioblastoma cell lines were investigated by immunohistochemistry, immunofluorescence, and cell biological experiments. Protein interactions were studied by immunoprecipitation, pull-down, and enzyme activity assays. CRN2 knock-out mice displayed neurological and behavioural alterations, e.g. reduced hearing sensitivity, reduced acoustic startle response, hypoactivity, and less frequent urination. While glioblastoma mice with or without the additional CRN2 knock-out allele exhibited no significant difference in their survival rates, the increased levels of CRN2 in transplanted glioblastoma cells caused a higher tumour cell encasement of murine brain slice capillaries. We identified two important factors of the tumour microenvironment, the tissue inhibitor of matrix metalloproteinase 4 (TIMP4) and the matrix metalloproteinase 14 (MMP14, synonym: MT1-MMP), as novel binding partners of CRN2. All three proteins mutually interacted and co-localised at the front of lamellipodia, and CRN2 was newly detected in exosomes. On the functional level, we demonstrate that CRN2 increased the secretion of TIMP4 as well as the catalytic activity of MMP14. Our results imply that CRN2 represents a pro-invasive effector within the tumour cell microenvironment of glioblastoma multiforme.

KEYWORDS:

Cancer; Coronin; Glioblastoma; Invasion; Metalloproteinases; Mouse model

PMID:
31677819
DOI:
10.1016/j.ejcb.2019.151046
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