title: The MEK-ERK pathway is necessary for serine phosphorylation of mitochondrial STAT3 and Ras-mediated transformation.
abstract: Activating mutations in the RasGTPases are the most common oncogenic lesions in human cancer. Similarly, elevated STAT3 expression and/or phosphorylation are observed in the majority of human cancers. We recently found that activated Ras requires a mitochondrial rather than a nuclear activity of STAT3 to support cellular transformation. This mitochondrial activity of STAT3 was supported by phosphorylation on serine 727 (S727) in the carboxyl-terminus of STAT3. In this study we show that the H-Ras oncoprotein engages the MEK-ERK pathway to drive phosphorylation of STAT3 on S727, while phosphoinositide 3-kinase (PI3K) and mTOR activity were superfluous. Moreover, pharmacological inhibition of MEK reduced transformation by H-, K- or N-Ras. However, cells expressing a mitochondrially restricted STAT3 with a phospho-mimetic mutation at S727 were partially resistant to inhibition of the ERK pathway, exhibiting a partial rescue of anchorage-independent cell growth in the presence of MEK inhibitor. This study shows that the MEK-ERK pathway is required for activated Ras-induced phosphorylation of STAT3 on S727, that inhibition of STAT3 S727 phosphorylation contributes to the anti-oncogenic potential of MEK inhibitors, and that mitochondrial STAT3 is one of the critical substrates of the Ras-MEK-ERK- axis during cellular transformation.
authors: New York University Langone School of Medicine, New York, NY, United States of America.
authors: Daniel J
authors: DJ
authors: Gough
authors: Lisa
authors: L
authors: Koetz
authors: David E
authors: DE
authors: Levy
mesh_terms: D016475:3T3 Cells; D000818:Animals; D002461:Cell Line, Transformed; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D015689:Oncogene Protein p21(ras) / Q000378:metabolism*; D010766:Phosphorylation; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D012694:Serine / Q000378:metabolism*
chemical_list: D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D012694:Serine; D015689:Oncogene Protein p21(ras)