title: p70 S6-kinase mediates the cooperation between Akt1 and Mek1 pathways in fibroblast-mediated extracellular matrix remodeling.
abstract: Previous studies have demonstrated both synergistic and opposing effects of Akt and Mek1/2 in various cell functions and disease states. Furthermore, Akt has been reported to inhibit and activate cRaf/Mek pathway, suggesting that their mutual interaction and cooperation may be cell type, stimuli and/or context specific. While PI3-kinase/Akt and cRaf/Mek pathways have been implicated in the regulation of extracellular matrix (ECM) remodeling, mutual interactions between these two pathways and their specific contributions to the events leading to ECM synthesis and assembly is not clear. We investigated the specific role of Akt1 and Mek1 in ECM synthesis and assembly by NIH 3T3 fibroblasts and how these effects were reconciled to mediate overall ECM remodeling. Our study identified that cooperation between Akt1 and Mek1 is necessary to mediate ECM synthesis. Whereas Akt1 activation resulted in Mek1 activation as evidenced by increased ERK1/2 phosphorylation, Mek1 inhibition using U0126 or DN-Mek1 resulted in enhanced Akt1 phosphorylation. Interestingly, both Akt1 and Mek1 activities were needed for the synthesis and assembly of ECM. The effect of Akt1 and Mek1 on ECM synthesis was reconciled through the activation of p70 S6-kinase via phosphorylation at T421/S424 and S411, respectively. Furthermore, Akt1 and Mek1 cooperated in mediating ECM assembly via activation of integrin β1. Together, we show for the first time that Akt1 and Mek1 pathways cooperate in the regulation of ECM remodeling by the fibroblasts.
authors.affiliation: Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, Charlie Norwood VA Medical Center, Augusta, GA, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Goc
authors.affiliation: Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, Charlie Norwood VA Medical Center, Augusta, GA, USA.
authors.forename: Harika
authors.initials: H
authors.lastname: Sabbineni
authors.affiliation: Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, Charlie Norwood VA Medical Center, Augusta, GA, USA.
authors.forename: Maha
authors.initials: M
authors.lastname: Abdalla
authors.affiliation: Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, Charlie Norwood VA Medical Center, Augusta, GA, USA; Department of Medicine and Vascular Biology Center, Georgia Regents University, Augusta, GA, USA. Electronic address: sshenoy@gru.edu.
authors.forename: Payaningal R
authors.initials: PR
authors.lastname: Somanath
mesh_terms: D000818:Animals; D005109:Extracellular Matrix / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005347:Fibroblasts / Q000201:enzymology*; D006801:Humans; D016023:Integrins / Q000378:metabolism; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D051379:Mice; D008954:Models, Biological; D041681:NIH 3T3 Cells; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D016326:Extracellular Matrix Proteins; D016023:Integrins; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D048369:MAP Kinase Kinase 1; C482127:Map2k1 protein, mouse
keywords: Akt1; Extracellular matrix; Integrin; Mek1; mTOR; p70 S6-kinase
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