Activation of either ERK1/2 or ERK5 MAP kinase pathways can lead to disruption of the actin cytoskeleton.
Oncogenic transformation often leads to the disruption of the actin cytoskeleton. Activation of the classical Ras-Raf-MEK1/2-ERK1/2 signalling cascade has been implicated in the effects of oncogenes such as Ras and Src on the cytoskeleton. Many of the studies of the effects of oncogenes on the cytoskeleton have made use of chemical inhibitors of MEK1/2 but it is now clear that these inhibitors also inactivate MEK5 in the MEK5-ERK5 MAP kinase pathway raising the possibility that this pathway may also be involved in oncogenic transformation. We therefore investigated whether activation of ERK5 can lead to disruption of the actin cytoskeleton. We show that activation of ERK5 can lead to loss of actin stress fibres, but by a distinct mechanism to ERK1/2. We demonstrate that ERK5 is activated by oncogenic Src as demonstrated by translocation of endogenous ERK5 from the cytoplasm to nucleus and activation of an ERK5-dependent transcriptional reporter and that ERK5 activation is required for Src-mediated transformation. We also show that in Src-transformed cells inhibition of ERK1/2 signalling is not sufficient for reappearance of the actin cytoskeleton and that ERK5 activation contributes to cytoskeletal disruption by Src. Our results suggest that multiple MAP kinase pathways downstream of oncogenes participate in cytoskeletal alterations.
Barros
Joana Castro
JC
Cancer Research UK Centre for Cell and Molecular Biology, Institute of Cancer Research, 237 Fulham Road, London, SW3 6JB, UK.
Marshall
Christopher J
CJ
D000199:Actins / Q000378:metabolism*; D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D003599:Cytoskeleton / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D017930:Genes, Reporter / Q000502:physiology; D006801:Humans; D048671:MAP Kinase Kinase 5 / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology*; D064326:MEF2 Transcription Factors; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism*; D048054:Mitogen-Activated Protein Kinase 7 / Q000235:genetics / Q000378:metabolism*; D018006:Myogenic Regulatory Factors; D041681:NIH 3T3 Cells; D021381:Protein Transport / Q000502:physiology; D022502:Stress Fibers / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation / Q000502:physiology; D014162:Transfection; D014170:Transformation, Genetic / Q000502:physiology; D020742:rhoA GTP-Binding Protein / Q000378:metabolism; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism
D000199:Actins; D004268:DNA-Binding Proteins; D064326:MEF2 Transcription Factors; D018006:Myogenic Regulatory Factors; D014157:Transcription Factors; D019061:src-Family Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048054:Mitogen-Activated Protein Kinase 7; D048671:MAP Kinase Kinase 5; C482565:Map2k5 protein, rat; D020742:rhoA GTP-Binding Protein