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Hough C , Radu M , Dore JJE
TGF-Beta Induced Erk Phosphorylation of Smad Linker Region Regulates Smad Signaling
PLoS One. 2012 Aug;7(8) :e42513
PMID: WOS:000307810000038    PMCID: PMC3412844    URL: http://www.ncbi.nlm.nih.gov/pubmed/22880011
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The Transforming Growth Factor-Beta (TGF-beta) family is involved in regulating a variety of cellular processes such as apoptosis, differentiation, and proliferation. TGF-beta binding to a Serine/Threonine kinase receptor complex causes the recruitment and subsequent activation of transcription factors known as smad2 and smad3. These proteins subsequently translocate into the nucleus to negatively or positively regulate gene expression. In this study, we define a second signaling pathway leading to TGF-beta receptor activation of Extracellular Signal Regulated Kinase (Erk) in a cell-type dependent manner. TGF-beta induced Erk activation was found in phenotypically normal mesenchymal cells, but not normal epithelial cells. By activating phosphotidylinositol 3-kinase (PI3K), TGF-beta stimulates p21-activated kinase2 (Pak2) to phosphorylate c-Raf, ultimately resulting in Erk activation. Activation of Erk was necessary for TGF-beta induced fibroblast replication. In addition, Erk phosphorylated the linker region of nuclear localized smads, resulting in increased half-life of C-terminal phospho-smad 2 and 3 and increased duration of smad target gene transcription. Together, these data show that in mesenchymal cell types the TGF-beta/PI3K/Pak2/Raf/MEK/Erk pathway regulates smad signaling, is critical for TGF-beta-induced growth and is part of an integrated signaling web containing multiple interacting pathways rather than discrete smad/non-smad pathways.
Hough, Chris Radu, Maria Dore, Jules J. E. Canadian Institutes of Health Research/Regional Partnership Program[ROP-62277, ROP-82355] This work was supported by funding through the Canadian Institutes of Health Research/Regional Partnership Program, ROP-62277 and ROP-82355. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. 52 Public library science San francisco 992wd