Akt (Protein Kinase B) Negatively Regulates SEK1 by Means of Protein Phosphorylation

Park, Hee Sae; Kim, Mi Sung; Huh, Sung Ho; Park, Jihyun; Chung, Jongkyeong; Kang, Sang Sun; Choi, Eui Ju

doi:10.1074/jbc.m110299200

Cited by 137 publications

(124 citation statements)

References 35 publications

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“…Recently, it has been reported that SEK1 activity is inhibited by insulin, and this leads to the inhibition of JNK activity (9). We have also observed that SEK1 kinase activity is inhibited by insulin (data not shown).…”

Section: Resultssupporting

confidence: 66%

“…It has also been shown that JNK pathway is down-regulated by insulin or IGF-1 treatments (9, 10), which results in greater cell survival (9). Therefore, we attempted to identify the molecule(s) in the JNK pathway that could be regulated by PI3KϪAKT signaling.…”

Section: Resultsmentioning

confidence: 99%

“…The activation of phosphatidylinositol 3-kinase (PI3K) correlates with increased cell survival, and this effect is largely mediated through the activation of a serine/threonine kinase, AKT (also known as PKB). PI3K agonists such as insulin and insulin-like growth factor-1 (IGF-1) have been shown to inhibit anisomycin and tumor necrosis factor-␣ (TNF-␣)-induced JNK activation (9,10). Earlier, we have shown that MLK3 is a potent activator of JNK pathway and that the activation of JNK by MLK3 is through direct phosphorylation and activation of SEK1/MKK4 (1,11).…”

mentioning

confidence: 99%

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Negative Regulation of Mixed Lineage Kinase 3 by Protein Kinase B/AKT Leads to Cell Survival

Barthwal¹,

Sathyanarayana²,

Kundu³

et al. 2003

Journal of Biological Chemistry

130

125

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Mixed lineage kinase 3 (MLK3) is a mitogen-activated protein kinase kinase kinase (MAPKKK) that activates c-jun N-terminal kinase (JNK) and can induce cell death in neurons. By contrast, the activation of phosphatidylinositol 3-kinase and AKT/protein kinase B (PKB) acts to suppress neuronal apoptosis. Here, we report a functional interaction between MLK3 and AKT1/PKB␣. Endogenous MLK3 and AKT1 interact in HepG2 cells, and this interaction is regulated by insulin. The interaction domain maps to the C-terminal half of MLK3 (amino acids 511-847), and this region also contains a putative AKT phosphorylation consensus sequence. Endogenous JNK, MKK7, and MLK3 kinase activities in HepG2 cells are significantly attenuated by insulin treatment, whereas the phosphatidylinositol 3-kinase inhibitors LY294002 and wortmannin reversed the effect. Finally, MLK3-mediated JNK activation is inhibited by AKT1. AKT phosphorylates MLK3 on serine 674 both in vitro and in vivo. Furthermore, the expression of activated AKT1 inhibits MLK3-mediated cell death in a manner dependent on serine 674 phosphorylation. Thus, these data provide the first direct link between MLK3-mediated cell death and its regulation by a cell survival signaling protein, AKT1.The cellular decision to undergo either cell death or cell survival is determined by the integration of multiple survival and death signals. Mixed lineage kinase 3 (MLK3) 1 is a member of a growing family of mixed lineage kinases (1). Recently, it has been shown that overexpression of MLK3 or NGF withdrawal leads to neuronal cell death, which can be prevented by treatment with a small molecule inhibitor of MLKs, CEP-1347 (2). Similarly, CEP-11004, an analog of CEP-1347, has also been shown to prevent neuronal cell death upon NGF withdrawal (3). These results indicate a significant and direct involvement of MLKs in regulating cell death; however, the detailed mechanism by which MLKs are regulated is still unknown.The c-jun-N-terminal kinase/stress-activated protein kinase (JNK/SAPK) is stimulated by proinflammatory cytokines, oxidative stress, heat shock, UV, ␥-irradiation, and by other cellular stresses (4, 5). The signals in stress-activated JNK pathway are transmitted through three core modules: MAP3Ks such as members of the mixed lineage kinases or MEKK members, a MAP2K such as SEK1/MKK4 or MKK7, and MAPK such as JNK family members (4, 5). The activated MAP3K phosphorylates and activates MKK7 or SEK1, which in turn phosphorylates and activates JNK. JNKs phosphorylate several nuclear transcription factors that include ELK1, c-Jun, and ATF2 (4, 5). In several cell types, the activation of JNKs is directly linked to cell death (6 -8). Therefore, one mechanism of cell survival could be to block JNK pathway induction. The activation of phosphatidylinositol 3-kinase (PI3K) correlates with increased cell survival, and this effect is largely mediated through the activation of a serine/threonine kinase, AKT (also known as PKB). PI3K agonists such as insulin and insulin-like growth factor-1 (IGF-1) ...

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Section: Resultssupporting

confidence: 66%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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Negative Regulation of Mixed Lineage Kinase 3 by Protein Kinase B/AKT Leads to Cell Survival

Barthwal¹,

Sathyanarayana²,

Kundu³

et al. 2003

Journal of Biological Chemistry

130

125

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“…A study by Park et al (21) shows that Akt (downstream of PI3K) can inhibit SEK and JNK. Gratton et al (53) have shown, in bovine aortic endothelial cells, that Akt phosphorylates and inactivates MEKK3 leading to a downregulation of MKK3/6 and p38 activity.…”

Section: Figmentioning

confidence: 99%

“…One possible role of PI3K activity is as a modulator of MAP kinase signaling. Akt, in some conditions, has been shown to negatively regulate c-Raf (part of the ERK pathway in some cells) (19), p38 (20), and stress-activated protein kinase kinase (upstream of JNK) (21).…”

mentioning

confidence: 99%

Phosphatidylinositol 3-Kinase Activity Negatively Regulates Stability of Cyclooxygenase 2 mRNA

Monick

Robeff

Butler

et al. 2002

Journal of Biological Chemistry

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Synergistic anti‐tumor effect of paclitaxel with CRM197, an inhibitor of HB‐EGF, in ovarian cancer

Yagi

Yotsumoto

Sonoda

et al. 2008

Intl Journal of Cancer

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Heparin-binding EGF-like growth factor (HB-EGF) plays a pivotal role in tumor growth and clinical outcomes in patients with ovarian cancer, leading to the validation of HB-EGF as a target for ovarian cancer therapy. In this study, we investigated the antitumor effects of paclitaxel, as an anti-cancer agent, and CRM197, as a specific inhibitor off HB-EGF, in ovarian cancer. Paclitaxel induced transient ERK activation and sustained activation of JNK and p38 MAPK through the ectodomain shedding of HB-EGF in SKOV3 cells. In addition, the overexpression of HB-EGF in paclitaxel-treated SKOV3 cells resulted in modulation of paclitaxelevoked MAPK signaling, including marked activation of ERK and Akt, and minimized activation of JNK and p38 MAPK, indicating that HB-EGF is involved in drug sensitivity through the balance of anti-apoptotic and pro-apoptotic signals induced by paclitaxel. The combination of paclitaxel with CRM197 had an inhibitory effect on cell proliferation and enhanced apoptosis via the inhibition of ERK and Akt activation and the stimulation of p38 and JNK activation. More prominently, the administration of paclitaxel with CRM197 resulted in synergistic anti-tumor effects in SKOV3 cells and in SKOV3 cells overexpressing HB-EGF in xenografted mice. Accordingly, inhibitory agents against HB-EGF, such as CRM197, represent possible chemotherapeutic and chemosensitizing agents for ovarian cancer.

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Akt (Protein Kinase B) Negatively Regulates SEK1 by Means of Protein Phosphorylation

Cited by 137 publications

References 35 publications

Negative Regulation of Mixed Lineage Kinase 3 by Protein Kinase B/AKT Leads to Cell Survival

Negative Regulation of Mixed Lineage Kinase 3 by Protein Kinase B/AKT Leads to Cell Survival

Phosphatidylinositol 3-Kinase Activity Negatively Regulates Stability of Cyclooxygenase 2 mRNA

Synergistic anti‐tumor effect of paclitaxel with CRM197, an inhibitor of HB‐EGF, in ovarian cancer

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