Universität zu Köln

Kelkar, Pranav, Walter, Anna, Papadopoulos, Symeon, Mross, Carmen, Munck, Martina, Peche, Vivek S. and Noegel, Angelika A. (2015). Nesprin-2 mediated nuclear trafficking and its clinical implications. Nucleus, 6 (6). S. 479 - 490. PHILADELPHIA: TAYLOR & FRANCIS INC. ISSN 1949-1042

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Abstract

Nuclear translocation of proteins has a crucial role in the pathogenesis of cancer, Alzheimer disease and viral infections. A complete understanding of nuclear trafficking mechanisms is therefore necessary in order to establish effective intervention strategies. Here we elucidate the role of Nesprin-2 in Ca2+/Calmodulin mediated nuclear transport. Nesprin-2 is an actin-binding nuclear envelope (NE) protein with roles in maintaining nuclear structure and location, regulation of transcription and mechanotransduction. Upon depletion of Nesprin-2 using shRNA, HaCaT cells show abnormal localization of the shuttling proteins BRCA1 and NF-B. We show that their nuclear transport is unlikely due to the canonical RAN mediated nuclear import, but rather to a RAN independent Ca2+/Calmodulin driven mechanism involving Nesprin-2. We report novel interactions between the actin-binding domain of Nesprin-2 and Calmodulin and between the NLS containing region of BRCA1 and Calmodulin. Strikingly, displacing Nesprins from the NE resulted in increased steady state Ca2+ concentrations in the cytoplasm suggesting a previously unidentified role of Nesprins in Ca2+ regulation. On comparing Nesprin-2 and BRCA1 localization in the ovarian cancer cell lines SKOV-3 and Caov-3, Nesprin-2 and BRCA1 were localized to the NE envelope and the nucleus in SKOV-3, respectively, and to the cytoplasm in Caov-3 cells. Fibroblasts obtained from EDMD5 (Emery Dreifuss muscular dystrophy) patients showed loss of Nesprin-2 from the nuclear envelope, corresponding reduced nuclear localization of BRCA1 and enhanced cytoplasmic Ca2+. Taken together, the data suggests a novel role of Nesprin-2 in Ca2+/Calmodulin mediated nuclear trafficking and provides new insights which can guide future therapies.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Kelkar, Pranav UNSPECIFIED UNSPECIFIED UNSPECIFIED Walter, Anna UNSPECIFIED UNSPECIFIED UNSPECIFIED Papadopoulos, Symeon UNSPECIFIED UNSPECIFIED UNSPECIFIED Mross, Carmen UNSPECIFIED UNSPECIFIED UNSPECIFIED Munck, Martina UNSPECIFIED UNSPECIFIED UNSPECIFIED Peche, Vivek S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Noegel, Angelika A. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-387397
DOI:	10.1080/19491034.2015.1128608
Journal or Publication Title:	Nucleus
Volume:	6
Number:	6
Page Range:	S. 479 - 490
Date:	2015
Publisher:	TAYLOR & FRANCIS INC
Place of Publication:	PHILADELPHIA
ISSN:	1949-1042
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language CALCIUM-DEPENDENT REGULATION; DNA-DAMAGE RESPONSE; MUSCULAR-DYSTROPHY; SEX REVERSAL; ENVELOPE; IMPORT; EXPORT; LOCALIZATION; ALPHA; SRY Multiple languages Cell Biology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/38739