Journal
FEBS LETTERS
Volume 584, Issue 11, Pages 2305-2310Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.febslet.2010.03.042
Keywords
Keratinocyte; Transforming growth factor-beta 1; Metalloproteinase-9; Rac1; Snail1; Mitogen-activated protein kinase; Epithelial-mesenchymal transition; Migration
Funding
- Fund for Science and Technology of Chile (FONDECYT) [1050476, 3000045]
- University of Chile (DID) [I003-99/2]
- Ministry of Science and Technological Development, Republic of Serbia [145048]
- Spanish Ministry of Science and Innovation [SAF2007-63821]
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Transforming growth factor-beta 1 (TGF-beta 1) activates Rac1 GTPase in mouse transformed keratinocytes. Expression of a constitutively active Q61LRac1 mutant induced an epithelial to mesenchymal transition (EMT) linked to stimulation of cell migration and invasion. On the contrary, expression of a dominant-negative N17TRac1 abolished TGF-beta 1-induced cell scattering, migration and invasion. Moreover, Q61LRac1 enhanced metalloproteinase-9 (MMP9) production to levels comparable to those induced by TGF-beta 1, while N17TRac1 was inhibitory. TGF-beta 1-mediated EMT involves the expression of the E-cadherin repressor Snail1, regulated by the Rac1 and mitogen-activated protein kinase (MAPK) pathways. Furthermore, MMP9 production was MAPK-dependent, as the MEK inhibitor PD98059 decreased TGF-beta 1-induced MMP9 expression and secretion in Q61LRac1 expressing cells. We propose that regulation of TGF-beta 1-mediated plasticity of transformed keratinocytes requires the cooperation between the Rac1 and MAPK signalling pathways. (C) 2010 Federation of European Biochemical Societies. Published by Elsevier B. V. All rights reserved.
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