A functional interaction between the MAGUK protein hDlg and the gap junction protein connexin 43 in cervical tumour cells.
Gap junctions, composed of Cxs (connexins), allow direct intercellular communication. Gap junctions are often lost during the development of malignancy, although the processes behind this are not fully understood. Cx43 is a widely expressed Cx with a long cytoplasmic C-terminal tail that contains several potential protein-interaction domains. Previously, in a model of cervical carcinogenesis, we showed that the loss of gap junctional communication correlated with relocalization of Cx43 to the cytoplasm late in tumorigenesis. In the present study, we demonstrate a similar pattern of altered expression for the hDlg (human discs large) MAGUK (membrane-associated guanylate kinase) family tumour suppressor protein in cervical tumour cells, with partial co-localization of Cx43 and hDlg in an endosomal/lysosomal compartment. Relocalization of these proteins is not due to a general disruption of cell membrane integrity or Cx targeting. Cx43 (via its C-terminus) and hDlg interact directly in vitro and can form a complex in cells. This novel interaction requires the N- and C-termini of hDlg. hDlg is not required for Cx43 internalization in W12GPXY cells. Instead, hDlg appears to have a role in maintaining a cytoplasmic pool of Cx43. These results demonstrate that hDlg is a physiologically relevant regulator of Cx43 in transformed epithelial cells.
MRC-University of Glasgow Centre for Virus Research, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TT, Scotland, UK.
Alasdair I
AI
Macdonald
Peng
P
Sun
Hegel
H
Hernandez-Lopez
Trond
T
Aasen
Malcolm B
MB
Hodgins
Michael
M
Edward
Sally
S
Roberts
Paola
P
Massimi
Miranda
M
Thomas
Lawrence
L
Banks
Sheila V
SV
Graham
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D018031:Connexin 43 / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D000074288:Discs Large Homolog 1 Protein; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D051528:Guanylate Kinases / Q000378:metabolism; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D034741:RNA, Small Interfering; D002583:Uterine Cervical Neoplasms / Q000378:metabolism* / Q000473:pathology
D048868:Adaptor Proteins, Signal Transducing; D018031:Connexin 43; C513314:DLG1 protein, human; D000074288:Discs Large Homolog 1 Protein; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D051528:Guanylate Kinases