Lysyl oxidase regulates actin filament formation through the p130(Cas)/Crk/DOCK180 signaling complex.
We have previously demonstrated that lysyl oxidase (LOX) is expressed in invasive breast cancer cells compared to poorly invasive cells. Additionally, we have recently shown that LOX regulates cell migration, a key step in the invasion process, through a hydrogen peroxide-dependent mechanism involving the focal adhesion kinase (FAK)/Src signaling complex. Here we further elucidate the role of LOX in cell motility/migration by examining the role of LOX in actin filament polymerization. We demonstrate that inhibition of LOX leads to an increase in phalloidin staining, directly associated with an increase in actin stress fiber formation. This increase in staining was confirmed by activity assays showing an increase in Rho activity with decreased LOX activity. Additionally, Rac and Cdc42 activity decreased with the reduction in LOX activity. Taken together, these data demonstrate a loss of a motogenic phenotype with decreased LOX activity. Finally, in order to elucidate the mechanism by which LOX regulates actin polymerization, we have demonstrated that LOX facilitates p130(Cas) phosphorylation, which allows for the binding to CAS related kinase (Crk) and formation of the p130(Cas)/Crk/DOCK180 signaling complex. Formation of this complex leads to an increase in Rac-GTP, which decreases actin stress fiber formation and increases formation of lamellipodium. These data demonstrate that LOX regulates cell motility/migration through changes in actin filament polymerization, which involve the regulation of the p130(Cas)/Crk/DOCK180 signaling pathway. Elucidating the role of LOX in the regulation of cell motility will allow the development of more effective therapeutic strategies to treat invasive/metastatic breast cancer.
Payne
Stacey L
SL
Children's Memorial Research Center, Cancer Biology and Epigenomics Program, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine at Northwestern University, Chicago, Illinois 60614, USA.
Hendrix
Mary J C
MJ
Kirschmann
Dawn A
DA
D008841:Actin Cytoskeleton / Q000378:metabolism*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D050719:Crk-Associated Substrate Protein / Q000378:metabolism*; D005260:Female; D006801:Humans; D046912:Multiprotein Complexes / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D008249:Protein-Lysine 6-Oxidase / Q000378:metabolism*; D050737:Proto-Oncogene Proteins c-crk / Q000378:metabolism*; D015398:Signal Transduction; D020744:rac GTP-Binding Proteins / Q000378:metabolism*
C485285:CRK protein, human; D050719:Crk-Associated Substrate Protein; C099818:DOCK1 protein, human; D046912:Multiprotein Complexes; D050737:Proto-Oncogene Proteins c-crk; D008249:Protein-Lysine 6-Oxidase; D020744:rac GTP-Binding Proteins