MEKK1 transduces activin signals in keratinocytes to induce actin stress fiber formation and migration.
Activins and other members of the transforming growth factor beta family play a critical role in morphological changes of the epidermis that require epithelial cell movement. We investigated the molecular pathways in the transmission of activin signals that lead to actin reorganization and epithelial cell migration. We found that activins cause the activation of RhoA but not of Rac and CDC42, leading to MEKK1-dependent phosphorylation of JNK and transcription factor c-Jun. Through a RhoA-independent mechanism, the activins also induce p38 activity in keratinocytes from wild-type but not from MEKK1-deficient mice. Although neither pathway is dependent on Smad activation, the MEKK1-mediated JNK and p38 activities are both essential for activin-stimulated and transcription-dependent keratinocyte migration. Only JNK is involved in transcription-independent actin stress fiber formation, which needs also the activity of ROCK. Because ROCK is required for JNK activation by RhoA and its overexpression leads to MEKK1 activation, we propose a RhoA-ROCK-MEKK1-JNK pathway and a MEKK1-p38 pathway as Smad-independent mechanisms in the transmission of activin signals. Together, these pathways lead to the control of actin cytoskeleton reorganization and epithelial cell migration, contributing to the physiologic and pathological effects of activins on epithelial morphogenesis.
Zhang
Lin
L
Department of Environmental Health, University of Cincinnati, 123 E. Shields St., Cincinnati, OH 45267-0056, USA.
Deng
Maoxian
M
Parthasarathy
Ranjani
R
Wang
Lei
L
Mongan
Maureen
M
Molkentin
Jeffery D
JD
Zheng
Yi
Y
Xia
Ying
Y
D000199:Actins / Q000378:metabolism*; D028341:Activins / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002465:Cell Movement; D003599:Cytoskeleton / Q000378:metabolism; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000166:cytology; D020558:GTP Phosphohydrolases / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D015603:Keratinocytes / Q000378:metabolism*; D048670:MAP Kinase Kinase 4; D048728:MAP Kinase Kinase Kinase 1 / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008856:Microscopy, Fluorescence; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D008954:Models, Biological; D009154:Mutation; D010766:Phosphorylation; D012190:Retroviridae / Q000235:genetics; D015398:Signal Transduction; D013997:Time Factors; D014945:Wound Healing; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D000199:Actins; D028341:Activins; D049452:Green Fluorescent Proteins; D006160:Guanosine Triphosphate; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D020558:GTP Phosphohydrolases; D020764:cdc42 GTP-Binding Protein; D020744:rac GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein