Mitogen-activated protein kinases, Erk and p38, phosphorylate and regulate Foxo1

Asada, Sachie; Daitoku, Hiroaki; Matsuzaki, Hitomi; Saito, Tomoko; Sudo, Tatsuhiko; Mukai, Hidehito; Iwashita, Shintaro; Kako, Koichiro; Kishi, Takashi; Kasuya, Yoshitoshi; Fukamizu, Akiyoshi

doi:10.1016/j.cellsig.2006.08.015

Cited by 218 publications

(188 citation statements)

References 42 publications

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“…Recently, ERK and p38 were shown to phosphorylate FOXO1. However, the functional outcomes were not discussed in the study 9 . On the other hand, overexpression of forkhead transcription factors (AFX and FKHR-L1) was shown to cause growth suppression in RASV12-transformed cells 34 .…”

Section: Discussionmentioning

confidence: 99%

ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation

et al. 2008

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The RAS-ERK pathway is known to play a pivotal role in differentiation, proliferation and tumour progression. Here, we show that ERK downregulates Forkhead box O 3a (FOXO3a) by directly interacting with and phosphorylating FOXO3a at Ser 294, Ser 344 and Ser 425, which NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript consequently promotes cell proliferation and tumorigenesis. The ERK-phosphorylated FOXO3a degrades via an MDM2-mediated ubiquitin-proteasome pathway. However, the nonphosphorylated FOXO3a mutant is resistant to the interaction and degradation by murine double minute 2 (MDM2), thereby resulting in a strong inhibition of cell proliferation and tumorigenicity. Taken together, our study elucidates a novel pathway in cell growth and tumorigenesis through negative regulation of FOXO3a by RAS-ERK and MDM2.The constitutive activation of certain signal transduction cascades leads to the development of tumours and the resistance of tumours to clinical therapy 1,2 . The RAS-ERK pathway triggers one of these cascades and governs many important functions, such as cell fate, differentiation, proliferation and survival in invertebrate and mammalian cells 3,4 . Human tumours frequently overexpress RAS or harbour activated RAS with a point mutation, which contributes substantially to tumour cell growth, invasion and angiogenesis 1, 2 , 5 -8. Cell plasma membrane receptor tyrosine kinases activate RAS GTPases, and GTP-bound RAS activates A-RAF, B-RAF and RAF-1 (ref. 10,17,18,21 , but the E3 ubiquitin ligase responsible for FOXO3a degradation has yet to be identified. MDM2, an E3 ubiquitin ligase plays an important role in the development of multiple human cancers through degrading tumour suppressor proteins, such as p53, RB and E-cadherin [22][23][24][25] . In addition, MDM2 has been shown to be regulated by the RAS-ERK signalling pathway 26 and blocking ERK activity with an MEK1 inhibitor, U0126, reduces MDM2 expression in breast cancer cells 27 .Here, we identify a novel pathway involving the downregulation of FOXO3a expression by RAS-ERK and MDM2, which leads to promotion of cell growth and tumorigenesis. We show that ERK interacts with and phosphorylates FOXO3a at Ser 294, Ser 344 and Ser 425; phosphorylation of FOXO3a at these residues increases FOXO3a-MDM2 interaction and enhances FOXO3a degradation via an MDM2-dependent ubiquitin-proteasome pathway. The non-phosphorylated FOXO3a-mimic mutant, compared to the phosphorylated FOXO3a-mimic mutant, exhibits more resistance to the interaction and degradation by MDM2, resulting in a strong inhibition of cell proliferation in vitro and tumorigenesis in vivo. RESULTS ERK suppresses FOXO3a stability and induces its nuclear exclusionThe RAS-ERK is an essential oncogenic signalling cascade that promotes tumour cell growth and development 8,28 . It was known that other oncogenic kinases, AKT and IKK, (Fig. 1b, c). Similarly, using Erk small interference RNA (siRNA) to knockdown ERK protein expression level in HeLa cells (Fig. 1d), or trea...

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Section: Discussionmentioning

confidence: 99%

ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation

et al. 2008

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“…Additional studies are required to elucidate the specific mechanism through which Erk regulates PDK4 mRNA, the levels of which have been shown to be controlled by numerous proteins and signaling pathways (Abbot et al 2005;Sugden and Holness 2006;Roche and Hiromasa 2007). Some transcriptional regulators of PDK4, such as retinoid X receptor and FOXO1, have previously been found to be negatively regulated by Erk signaling (Arnaud et al 2004;Coll et al 2006;Asada et al 2007;Burgermeister et al 2007;Macoritto et al 2008;Shankar et al 2008;Meng et al 2011). Importantly, previous studies implicating PI3K/Akt as a negative regulator of PDK4 expression were performed in myocytes (Puthanveetil et al 2010), which must generate significant energy (i.e., ATP) from glucose in response to insulin to function properly (Latronico et al 2004).…”

Section: Discussionmentioning

confidence: 99%

Erk regulation of pyruvate dehydrogenase flux through PDK4 modulates cell proliferation

Grassian¹,

Metallo²,

Coloff³

et al. 2011

Genes Dev.

172

137

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Loss of extracellular matrix (ECM) attachment leads to metabolic impairments that limit cellular energy production. Characterization of the metabolic alterations induced by ECM detachment revealed a dramatic decrease in uptake of glucose, glutamine, and pyruvate, and a consequent decrease in flux through glycolysis, the pentose phosphate pathway, and the tricarboxylic acid (TCA) cycle. However, flux through pyruvate dehydrogenase (PDH) is disproportionally decreased, concomitant with increased expression of the PDH inhibitory kinase, PDH kinase 4 (PDK4), and increased carbon secretion. Overexpression of ErbB2 maintains PDH flux by suppressing PDK4 expression in an Erk-dependent manner, and Erk signaling also regulates PDH flux in ECMattached cells. Additionally, epidermal growth factor (EGF), a potent inducer of Erk, positively regulates PDH flux through decreased PDK4 expression. Furthermore, overexpression of PDK4 in ECM-detached cells suppresses the ErbB2-mediated rescue of ATP levels, and in attached cells, PDK4 overexpression decreases PDH flux, de novo lipogenesis, and cell proliferation. Mining of microarray data from human tumor data sets revealed that PDK4 mRNA is commonly down-regulated in tumors compared with their tissues of origin. These results identify a novel mechanism by which ECM attachment, growth factors, and oncogenes modulate the metabolic fate of glucose by controlling PDK4 expression and PDH flux to influence proliferation.

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“…MAPKs include three members, ERK, JNK and p38. Under oxidative stress, FOXO1 is phosphorylated by ERK and p38 cooperatively (44). Accordingly, p38 can induce phosphorylation of FOXO3 following treatment with doxorubicin (45).…”

Section: Mammalian Sterile 20-like Kinase (Mst) and Jun-n-terminal Kimentioning

confidence: 99%

Post-translational modifications of FOXO family proteins

Wang

Huang

2016

Molecular Medicine Reports

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Abstract. The Forkhead box O (FOXO) protein family is predominantly involved in apoptosis, oxidative stress, DNA damage/repair, tumor angiogenesis, glycometabolism, regulating life span and other important biological processes. Its activity is affected by a variety of posttranslational modifications (PTMs), including phosphorylation, acetylation, ubiquitination, methylation and glycosylation. When cells are subjected to different environments, the corresponding PTMs act on the FOXO protein family, to change transcriptional activity or subcellular localization, and the expression of downstream target genes, will ultimately affect the biological behavior of the cells. In this review, we will discuss the biological characteristics of FOXO protein PTMs.

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Mitogen-activated protein kinases, Erk and p38, phosphorylate and regulate Foxo1

Cited by 218 publications

References 42 publications

ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation

ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation

Erk regulation of pyruvate dehydrogenase flux through PDK4 modulates cell proliferation

Post-translational modifications of FOXO family proteins

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