The dioxin receptor regulates the constitutive expression of the vav3 proto-oncogene and modulates cell shape and adhesion.
The dioxin receptor (AhR) modulates cell plasticity and migration, although the signaling involved remains unknown. Here, we report a mechanism that integrates AhR into these cytoskeleton-related functions. Immortalized and mouse embryonic fibroblasts lacking AhR (AhR-/-) had increased cell area due to spread cytoplasms that reverted to wild-type morphology upon AhR re-expression. The AhR-null phenotype included increased F-actin stress fibers, depolarized focal adhesions, and enhanced spreading and adhesion. The cytoskeleton alterations of AhR-/- cells were due to down-regulation of constitutive Vav3 expression, a guanosine diphosphate/guanosine triphosphate exchange factor for Rho/Rac GTPases and a novel transcriptional target of AhR. AhR was recruited to the vav3 promoter and maintained constitutive mRNA expression in a ligand-independent manner. Consistently, AhR-/- fibroblasts had reduced Rac1 activity and increased activation of the RhoA/Rho kinase (Rock) pathway. Pharmacological inhibition of Rac1 shifted AhR+/+ fibroblasts to the null phenotype, whereas Rock inhibition changed AhR-null cells to the AhR+/+ morphology. Knockdown of vav3 transcripts by small interfering RNA induced cytoskeleton defects and changes in adhesion and spreading mimicking those of AhR-null cells. Moreover, vav3-/- MEFs, as AhR-/- mouse embryonic fibroblasts, had increased cell area and enhanced stress fibers. By modulating Vav3-dependent signaling, AhR could regulate cell shape, adhesion, and migration under physiological conditions and, perhaps, in certain pathological states.
Carvajal-Gonzalez
Jose M
JM
Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias, Universidad de Extremadura, 06071 Badajoz, Spain.
Mulero-Navarro
Sonia
S
Roman
Angel Carlos
AC
Sauzeau
Vincent
V
Merino
Jaime M
JM
Bustelo
Xose R
XR
Fernandez-Salguero
Pedro M
PM
D000199:Actins / Q000378:metabolism; D000818:Animals; D002448:Cell Adhesion; D048430:Cell Shape; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D051567:Proto-Oncogene Proteins c-vav / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D018336:Receptors, Aryl Hydrocarbon / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D000199:Actins; D051567:Proto-Oncogene Proteins c-vav; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; C496622:Vav3 protein, mouse; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein