Matricellular protein CCN3 (NOV) regulates actin cytoskeleton reorganization.
CCN3 (NOV), a putative ligand for integrin receptors, is tightly associated with the extracellular matrix and mediates diverse cellular functions, including cell adhesion and proliferation. CCN3 has been shown to negatively regulate growth although it promotes migration in a cell type-specific manner. In this study, overexpression of CCN3 reduces growth and increases intercellular adhesion of breast cancer cells. Interestingly, CCN3 overexpression also led to the formation of multiple pseudopodia that are enriched in actin, CCN3, and vinculin. Breast cancer cells preincubated with exogenous CCN3 protein also induced the same phenotype, indicating that secreted CCN3 is sufficient to induce changes in cell morphology. Surprisingly, extracellular CCN3 is internalized to the early endosomes but not to the membrane protrusions, suggesting pseudopodia-enriched CCN3 may derive from a different source. The presence of an intracellular variant of CCN3 will be consistent with our finding that the cytoplasmic tail of the gap junction protein connexin43 (Cx43) associates with CCN3. Cx43 is a channel protein permitting intercellular communication to occur. However, neither the channel properties nor the protein levels of Cx43 are affected by the CCN3 protein. In contrast, CCN3 proteins are down-regulated in the absence of Cx43. Finally, we showed that overexpression of CCN3 increases the activity of the small GTPase Rac1, thereby revealing a pathway that links Cx43 directly to actin reorganization.
Sin
Wun-Chey
WC
Department of Cellular and Physiological Sciences and The Life Sciences Institute, University of British Columbia, Vancouver, British Columbia V6T1Z3, Canada. wcsin@interchange.ubc.ca
Tse
Mimi
M
Planque
Nathalie
N
Perbal
Bernard
B
Lampe
Paul D
PD
Naus
Christian C
CC
D000199:Actins / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion / Q000235:genetics; D045744:Cell Line, Tumor; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism*; D003599:Cytoskeleton / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D008297:Male; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D055514:Nephroblastoma Overexpressed Protein / Q000235:genetics / Q000378:metabolism*; D011554:Pseudopodia / Q000235:genetics / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
D000199:Actins; C526319:CCN3 protein, human; D018031:Connexin 43; D009363:Neoplasm Proteins; D055514:Nephroblastoma Overexpressed Protein; C107953:RAC1 protein, human; D020830:rac1 GTP-Binding Protein
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