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

Solga R, Behrens J, Ziemann A, Riou A, Berwanger C, Becker L, Garrett L, de Angelis MH, Fischer L, Coras R, Barkovits K, Marcus K, Mahabir E, Eichinger L, Schröder R, Noegel AA, Clemen CS (2019)

Publication Type: Journal article

Publication year: 2019

Journal

European Journal of Cell Biology Elsevier

Article Number: 151046

DOI: 10.1016/j.ejcb.2019.151046

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.

Authors with CRIS profile

Rolf Schröder Professur für Neuropathologie

Involved external institutions

Ruhr-Universität Bochum (RUB) DE Germany (DE) Universität zu Köln DE Germany (DE) Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (HMGU) / Helmholtz Munich DE Germany (DE) Max-Planck-Institut für Stoffwechselforschung / Max Planck Institute for Metabolism Research DE Germany (DE)

How to cite

APA:

Solga, R., Behrens, J., Ziemann, A., Riou, A., Berwanger, C., Becker, L.,... Clemen, C.S. (2019). CRN2 binds to TIMP4 and MMP14 and promotes perivascular invasion of glioblastoma cells. European Journal of Cell Biology. https://doi.org/10.1016/j.ejcb.2019.151046

MLA:

Solga, Roxana, et al. "CRN2 binds to TIMP4 and MMP14 and promotes perivascular invasion of glioblastoma cells." European Journal of Cell Biology (2019).

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