Solga, Roxana, Behrens, Juliane, Ziemann, Anja, Riou, Adrien, Berwanger, Carolin, Becker, Lore ORCID: 0000-0002-6890-4984, Garrett, Lillian ORCID: 0000-0003-4880-7076, de Angelis, Martin Hrabe ORCID: 0000-0002-7898-2353, Fischer, Lisa, Coras, Roland, Barkovits, Katalin, Marcus, Katrin, Mahabir, Esther, Eichinger, Ludwig ORCID: 0000-0003-1594-6117, Schroeder, Rolf, Noegel, Angelika A., Clemen, Christoph S., Aguilar-Pimentel, Antonio, Schmidt-Weber, Carsten, Klopstock, Thomas, Adler, Thure, Treisel, Irina, Busch, Dirk H., Moreth, Kristin, Hoelter, Sabine M., Zimprich, Annemarie, Wurst, Wolfgang, Amarie, Oana, Graw, Jochen, Rozman, Jan, Calzada-Wack, Julia, Racz, Ildiko, Rathkolb, Birgit, Wolf, Eckhard, Oestereicher, Manuela, Miller, Gregor, Lengger, Christoph, Maier, Holger, Stoeger, Claudia, Leuchtenberger, Stefanie, Gallus-Durner, Valerie and Fuchs, Helmut (2019). CRN2 binds to TIMP4 and MMP14 and promotes perivascular invasion of glioblastoma cells. Eur. J. Cell Biol., 98 (5-8). MUNICH: ELSEVIER GMBH. ISSN 1618-1298

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Solga, RoxanaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Behrens, JulianeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ziemann, AnjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Riou, AdrienUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Berwanger, CarolinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Becker, LoreUNSPECIFIEDorcid.org/0000-0002-6890-4984UNSPECIFIED
Garrett, LillianUNSPECIFIEDorcid.org/0000-0003-4880-7076UNSPECIFIED
de Angelis, Martin HrabeUNSPECIFIEDorcid.org/0000-0002-7898-2353UNSPECIFIED
Fischer, LisaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Coras, RolandUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Barkovits, KatalinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Marcus, KatrinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mahabir, EstherUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Eichinger, LudwigUNSPECIFIEDorcid.org/0000-0003-1594-6117UNSPECIFIED
Schroeder, RolfUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Noegel, Angelika A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Clemen, Christoph S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Aguilar-Pimentel, AntonioUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmidt-Weber, CarstenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Klopstock, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Adler, ThureUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Treisel, IrinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Busch, Dirk H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moreth, KristinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoelter, Sabine M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zimprich, AnnemarieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wurst, WolfgangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Amarie, OanaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Graw, JochenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rozman, JanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Calzada-Wack, JuliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Racz, IldikoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rathkolb, BirgitUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wolf, EckhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Oestereicher, ManuelaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Miller, GregorUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lengger, ChristophUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Maier, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stoeger, ClaudiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Leuchtenberger, StefanieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gallus-Durner, ValerieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fuchs, HelmutUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-126166
DOI: 10.1016/j.ejcb.2019.151046
Journal or Publication Title: Eur. J. Cell Biol.
Volume: 98
Number: 5-8
Date: 2019
Publisher: ELSEVIER GMBH
Place of Publication: MUNICH
ISSN: 1618-1298
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
TYPE-1 MATRIX-METALLOPROTEINASE; TISSUE INHIBITOR; EXPRESSION; PROTEIN; CORONIN; MECHANISMS; PHOSPHORYLATION; INVADOPODIA; REGULATORS; SECRETIONMultiple languages
Cell BiologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/12616

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