Correction: 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.

Novel STAT3 Inhibitor LDOC1 Targets Phospho-JAK2 for Degradation by Interacting with LNX1 and Regulates the Aggressiveness of Lung Cancer

“…The importance of phosphorylated STAT3 S727 (pSTAT3 S727 ) has been observed; pSTAT3 S727 is highly enriched in mitochondria than that present in the cytoplasm [42,43], and the activities of mitochondrial STAT3 (mitoSTAT3) are supported by phosphorylation on STAT3 S727 [43]. The discovery of mitoSTAT3 opened up a new avenue through which STAT3 may regulate cell metabolism and mitochondrial gene expression [42,44].…”

A STAT3 of Addiction: Adipose Tissue, Adipocytokine Signalling and STAT3 as Mediators of Metabolic Remodelling in the Tumour Microenvironment

“…Nonetheless, post-translational modifications activated downstream of cytokines, growth factors and oncogenes shape the sub-cellular localization and activities of STAT3 both in cancer and normal cells. In addition to Y705P, STAT3 can also undergo several other post-translational modifications such as phosphorylation on S727 in oncogenic transformation [79,80], lysine acetylation or methylation and cysteine oxidation or glutathionylation in starved cancer cells stimulated with serum or insulin, and in cardiomyocytes as part of reduction-oxidation (REDOX) regulation [81][82][83]. Serine 727 phosphorylated STAT3 (pS727 STAT3) exhibits distinct mitochondrial localization and non-transcriptional function through the modulation of the activity of the electron transport chain (ETC) and the mitochondrial permeability transition pores (MPTP) [1,84].…”

“…Direct mitochondrial metabolic remodeling through the activity of STAT3 was shown via the serine phosphorylation of mitochondrial STAT3; a RAS/MEK/ERK mediated transformation in a mouse model through the modulation of aerobic glycolysis and ETC activity [79,91]. The nuclear influence of canonically activated STAT3 on metabolism was shown to promote a shift towards glycolysis through HIF-1α-induced pyruvate kinase M2 isoform (PKM2) chronic activation of STAT3; this in turn activates HIF-1α; this positive feedback loop supports proliferative and pro-survival phenotypes [48,49,99].…”

Ischemia Reperfusion Injury: Mechanisms of Damage/Protection and Novel Strategies for Cardiac Recovery/Regeneration

“…Tumor Necrosis Factor Receptor-2 (TNFR2), via Janus Kinase (JAK), is the most relevant mediator of STAT3 activation in cardiomyocyte [68,69,70,71,72]. Moreover, it has been reported that the activation of ERK [40,41] and the inhibition of Forkhead Box O-1 (FOXO-1) [69] contribute to the cross-talk between the RISK and the SAFE pathway [73,74]. However, as the SAFE pathway in humans is under the control of STAT5, the role of STAT3 in this pathway is still a matter of debate [75].…”