Raf-MEK-Erk cascade in anoikis is controlled by Rac1 and Cdc42 via Akt.
Signals from the extracellular matrix are essential for the survival of many cell types. Dominant-negative mutants of two members of Rho family GTPases, Rac1 and Cdc42, mimic the loss of anchorage in primary mouse fibroblasts and are potent inducers of apoptosis. This pathway of cell death requires the activation of both the p53 tumor suppressor and the extracellular signal-regulated mitogen-activated protein kinases (Erks). Here we characterize the proapoptotic Erk signal and show that it differs from the classically observed survival-promoting one by the intensity of the kinase activation. The disappearance of the GTP-bound forms of Rac1 and Cdc42 gives rise to proapoptotic, moderate activation of the Raf-MEK-Erk cascade via a signaling pathway involving the kinases phosphatidlyinositol 3-kinase and Akt. Moreover, concomitant activation of p53 and inhibition of Akt are both necessary and sufficient to signal anoikis in primary fibroblasts. Our data demonstrate that the GTPases of the Rho family control three major components of cellular signal transduction, namely, p53, Akt, and Erks, which collaborate in the induction of apoptosis due to the loss of anchorage.
Zugasti
O
O
Institut de Génétique Moléculaire, CNRS UMR5535, F-34293 Montpellier Cedex 5, France.
Rul
W
W
Roux
P
P
Peyssonnaux
C
C
Eychene
A
A
Franke
T F
TF
Fort
P
P
Hibner
U
U
D000818:Animals; D023102:Anoikis; D017209:Apoptosis; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D005109:Extracellular Matrix / Q000502:physiology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D048369:MAP Kinase Kinase 1; D020935:MAP Kinase Signaling System; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D020764:cdc42 GTP-Binding Protein / Q000235:genetics / Q000502:physiology; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000502:physiology; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000502:physiology*
D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D019908:Proto-Oncogene Proteins c-raf; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; C482127:Map2k1 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein; D020741:rho GTP-Binding Proteins