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J Cell Sci. 2017 Sep 1;130(17):2867-2882. doi: 10.1242/jcs.202408. Epub 2017 Jul 21.

The E3 ubiquitin ligase NEDD4 induces endocytosis and lysosomal sorting of connexin 43 to promote loss of gap junctions.

Totland MZ1,2,3,4, Bergsland CH1,2,3,4, Fykerud TA1,2,4, Knudsen LM1,2,3,4, Rasmussen NL1,2,3,4, Eide PW1,2,4, Yohannes Z1,2,4, Sørensen V2,4,5, Brech A2,3,5,6, Lothe RA1,2,3,4, Leithe E7,2,4.

Author information

1
Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, 0424 Oslo, Norway.
2
Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, 0316 Oslo, Norway.
3
Institute for Biosciences, University of Oslo, 0316 Oslo, Norway.
4
K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, 0424 Oslo, Norway.
5
Department of Core Facilities, Institute for Cancer Research, Oslo University Hospital, 0424 Oslo, Norway.
6
Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, 0424 Oslo, Norway.
7
Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, 0424 Oslo, Norway eleithe@rr-research.no.

Abstract

Intercellular communication via gap junctions has an important role in controlling cell growth and in maintaining tissue homeostasis. Connexin 43 (Cx43; also known as GJA1) is the most abundantly expressed gap junction channel protein in humans and acts as a tumor suppressor in multiple tissue types. Cx43 is often dysregulated at the post-translational level during cancer development, resulting in loss of gap junctions. However, the molecular basis underlying the aberrant regulation of Cx43 in cancer cells has remained elusive. Here, we demonstrate that the oncogenic E3 ubiquitin ligase NEDD4 regulates the Cx43 protein level in HeLa cells, both under basal conditions and in response to protein kinase C activation. Furthermore, overexpression of NEDD4, but not a catalytically inactive form of NEDD4, was found to result in nearly complete loss of gap junctions and increased lysosomal degradation of Cx43 in both HeLa and C33A cervical carcinoma cells. Collectively, the data provide new insights into the molecular basis underlying the regulation of gap junction size and represent the first evidence that an oncogenic E3 ubiquitin ligase promotes loss of gap junctions and Cx43 degradation in human carcinoma cells.

KEYWORDS:

Cancer; Connexin; Degradation; Gap junction; NEDD4; Ubiquitin

PMID:
28733455
DOI:
10.1242/jcs.202408
[Indexed for MEDLINE]
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