Loss of cell-cell contacts induces NF-kappaB via RhoA-mediated activation of protein kinase D1.
Cell-cell contacts mediated by cadherins are known to inhibit the small Rho-GTPase RhoA. We here show that in epithelial cells the disruption of these cell-cell contacts as mediated by a calcium switch leads to actin re-organization and the activation of RhoA. We identified the serine/threonine kinase protein kinase D1 (PKD1) as a downstream target for RhoA in this pathway. After disruption of cell-cell contacts, PKD1 relayed RhoA activation to the induction of the transcription factor NF-kappaB. We found that a signaling complex composed of the kinases ROCK, novel protein kinase C (nPKC), and Src family kinases (SFKs) is upstream of PKD1 and crucial for RhoA-mediated NF-kappaB activation. In conclusion, our data suggest a previously undescribed signaling pathway of how RhoA is activated by loss of cell-cell adhesions and by which it mediates the activation of NF-kappaB. We propose that this pathway is of relevance for epithelial tumor cell biology, where loss of cell-cell contacts has been implicated in regulating cell survival and motility.
Cowell
Catherine F
CF
Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Jacksonville, Florida 32224, USA.
Yan
Irene K
IK
Eiseler
Tim
T
Leightner
Amanda C
AC
Döppler
Heike
H
Storz
Peter
P
D002450:Cell Communication; D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D046912:Multiprotein Complexes; D016328:NF-kappa B / Q000235:genetics*; D011493:Protein Kinase C / Q000378:metabolism*; D015398:Signal Transduction; D015533:Transcriptional Activation; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
D046912:Multiprotein Complexes; D016328:NF-kappa B; C089212:protein kinase D; D011493:Protein Kinase C; D020742:rhoA GTP-Binding Protein