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Molecular and Cellular Biology, January 2005, p. 60-65, Vol. 25, No. 1
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.1.60-65.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

MEKK1 Transduces Activin Signals in Keratinocytes To Induce Actin Stress Fiber Formation and Migration

Lin Zhang,1,{dagger} Maoxian Deng,1 Ranjani Parthasarathy,1 Lei Wang,2 Maureen Mongan,1 Jeffery D. Molkentin,3,4 Yi Zheng,2 and Ying Xia1,3*

Department of Environmental Health,1 Center for Environmental Genetics, University of Cincinnati Medical Center,3 and Division of Experimental Hematology,2 Divisions of Molecular Cardiovascular Biology and Cardiology, Children's Hospital Medical Center, Cincinnati, Ohio4

Received 5 April 2004/ Returned for modification 2 June 2004/ Accepted 4 October 2004

Activins and other members of the transforming growth factor ß 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.

* Corresponding author. Mailing address: Department of Environmental Health, University of Cincinnati, 123 E. Shields St., Cincinnati, OH 45267-0056. Phone: (513) 558-0371. Fax: (513) 558-0974. E-mail: xiay{at}.uc.edu.

{dagger} Present address: Department of Central Lab, Southern Medical University, Tonghe, Guangzhou, People's Republic of China.

Molecular and Cellular Biology, January 2005, p. 60-65, Vol. 25, No. 1
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.1.60-65.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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