COX2 expression and Erk1/Erk2 activity mediate Cot-induced cell migration.
The MAPKKK8 Cot/tpl-2, identified as an oncogene (Cot-T), participates in the intracellular signaling activated by members of the TLR and TNFalpha receptor superfamilies. Here we demonstrate that Cot promotes cell migration by regulating different steps involved in this process, such as cell adhesion and metalloproteinase activity. Indeed, Cot also regulates the cytoskeleton and Cot-T overexpression provokes the polarization of microtubules and the loss of stress fibers. Moreover, and in accordance with the increased Rac-GTP levels observed, Cot-T overexpressing cells develop more lamellipodia than control cells. Conversely, depletion of endogenous Cot increases the formation of stress fibers which is correlated with the high levels of Rho-GTP observed in these cells. In addition, the increase in COX2 expression and the activation of Erk1/2 regulated by Cot are essential for the induction of cell migration. Together, these data provide evidence of a new role for both proto-oncogenic and oncogenic Cot.
Instituto de Investigaciones Biomédicas, Dpto. de Bioquímica, UAM, Arturo Duperier 4, 28029 Madrid, Spain.
Cristina
C
Rodríguez
Pilar
P
López
Maite
M
Pozo
Antonio Martín
AM
Duce
Marta
M
López-Pelaéz
Margarita
M
Fernández
Susana
S
Alemany
D000818:Animals; D002465:Cell Movement; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000378:metabolism*; D003599:Cytoskeleton / Q000201:enzymology; D004790:Enzyme Induction; D006367:HeLa Cells; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D020744:rac GTP-Binding Proteins / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D011518:Proto-Oncogene Proteins; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020930:MAP Kinase Kinase Kinases; C069937:MAP3K8 protein, human; D020744:rac GTP-Binding Proteins; D020741:rho GTP-Binding Proteins