Negative regulation of the serine/threonine kinase B-Raf by Akt

Guan, Kun Liang; Figueroa, Claudia; Brtva, Teresa R.; Zhu, Tianquan; Taylor, Jennifer; Barber, Theodore D.; Vojtek, Anne B.

doi:10.1074/jbc.m004371200

Cited by 137 publications

(139 citation statements)

References 21 publications

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“…Treatment of PC3 cells with a specific Akt inhibitor caused a marked dosedependent increase in ERK phosphorylation (Fig 4b), compatible with an element of crosstalk between the ERK and PI3kinase pathways. 39,40 In the context of the previous results (Fig 2) showing reduced survival of IGF1R siRNA-transfected PC3 cells, the enhancement of ERK phosphorylation may be consistent with a role for MAPK in apoptosis induction in these cells. 41 Serial monitoring of the IGF response indicated that this was a transient effect, apparent 48 hours after transfection, and followed by profound inhibition of IGF-induced activation of ERKs, p38, and Akt (Fig 4c).…”

Section: Effects Of Igf1r Knockdown On Phosphorylation Of Signalling supporting

confidence: 82%

Silencing of the IGF1R gene enhances sensitivity to DNA-damaging agents in both PTEN wild-type and mutant human prostate cancer

et al. 2004

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The type 1 insulin-like growth factor receptor (IGF1R) is overexpressed in prostate cancer, and mediates proliferation, motility, and survival. Many prostate cancers harbor inactivating PTEN mutations, enhancing Akt phosphorylation. This activates the principal antiapoptotic pathway downstream of the IGF1R, calling into question the value of IGF1R targeting in this tumor. The aim of the current study was to assess the effect of IGF1R gene silencing in prostate cancer cells that lack functional PTEN protein. In human DU145, LNCaP and PC3 prostate cancer cells, transfection with IGF1R small interfering RNA induced significant enhancement of apoptosis and inhibition of survival, not only in PTEN wild-type DU145 but also in PTEN mutant LNCaP and PC3. This was attributed to attenuation of IGF signaling via Akt, ERKs and p38. In both DU145 and PC3, IGF1R knockdown led to enhancement of sensitivity to mitoxantrone, etoposide, nitrogen mustard and ionizing radiation. There was no sensitization to paclitaxel or 5-fluorouracil, which do not damage DNA, suggesting that chemosensitization results from impairment of the DNA damage response, in addition to removal of apoptosis protection. These results support the concept of IGF1R targeting in prostate cancer, and indicate that PTEN loss does not render tumor cells refractory to this strategy.

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Section: Effects Of Igf1r Knockdown On Phosphorylation Of Signalling supporting

confidence: 82%

Silencing of the IGF1R gene enhances sensitivity to DNA-damaging agents in both PTEN wild-type and mutant human prostate cancer

et al. 2004

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“…Alternatively, Akt has been shown to phosphorylate Raf-1, leading to the downregulation of the ERK pathway in phorbol 12-myristate 13-acetate-stimulated MCF-7 cells or in differentiated myotubes (Rommel et al, 1999). B-Raf activity is also inhibited by epidermal growth factor-induced Akt stimulation (Guan et al, 2000). Our study reveals an additional mechanism, because we show that overexpressed Akt down-regulated ERK/Elk-1-dependent transcriptional activity, an effect that was undetectable under endogenous Akt activation.…”

Section: Discussionmentioning

confidence: 99%

Akt Down-Regulates ERK1/2 Nuclear Localization and Angiotensin II-induced Cell Proliferation through PEA-15

Gervais

Dugourd

Muller

et al. 2006

MBoC

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Angiotensin II (AngII) type 1 receptors (AT1) regulate cell growth through the extracellular signal-regulated kinase (ERK)1/2 and phosphatidylinositol 3-kinase (PI3K) pathways. ERK1/2 and Akt/protein kinase B, downstream of PI3K, are independently activated but both required for mediating AngII-induced proliferation when expressed at endogenous levels. We investigate the effect of an increase in the expression of wild-type Akt1 by using Chinese hamster ovary (CHO)-AT1 cells. Unexpectedly, Akt overexpression inhibits the AT1-mediated proliferation. This effect could be generated by a cross-talk between the PI3K and ERK1/2 pathways. A functional partner is the phosphoprotein enriched in astrocytes of 15 kDa (PEA-15), an Akt substrate known to bind ERK1/2 and to regulate their nuclear translocation. We report that Akt binds to PEA-15 and that Akt activation leads to PEA-15 stabilization, independently of PEA-15 interaction with ERK1/2. Akt cross-talk with PEA-15 does not affect ERK1/2 activation but decreases their nuclear activity as a result of the blockade of ERK1/2 nuclear accumulation. In response to AngII, PEA-15 overexpression displays the same functional consequences on ERK1/2 signaling as Akt overactivation. Thus, Akt overactivation prevents the nuclear translocation of ERK1/2 and the AngII-induced proliferation through interaction with and stabilization of endogenous PEA-15.

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“…Akt can phosphorylate Raf-1 and B-Raf and leads to their inactivation. [188][189][190][191] Akt can also activate Raf-1 through a Rasindependent but PKC-dependent mechanism that results in the prevention of apoptosis. 192 Suppression of apoptosis in some cells by Raf and MEK requires PI3K-dependent signals.…”

Section: Overview Of Jak/stat Pathwaymentioning

confidence: 99%

Contributions of the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways to leukemia

et al. 2008

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Mutations and chromosomal translocations occur in leukemic cells that result in elevated expression or constitutive activation of various growth factor receptors and downstream kinases. The Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways are often activated by mutations in upstream genes. The Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways are regulated by upstream Ras that is frequently mutated in human cancer. Recently, it has been observed that the FLT-3 and Jak kinases and the phosphatase and tensin homologue deleted on chromosome 10 ( PTEN) phosphatase are also frequently mutated or their expression is altered in certain hematopoietic neoplasms. Many of the events elicited by the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways have direct effects on survival pathways. Aberrant regulation of the survival pathways can contribute to uncontrolled cell growth and lead to leukemia. In this review, we describe the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT signaling cascades and summarize recent data regarding the regulation and mutation status of these pathways and their involvement in leukemia

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Negative regulation of the serine/threonine kinase B-Raf by Akt

Cited by 137 publications

References 21 publications

Silencing of the IGF1R gene enhances sensitivity to DNA-damaging agents in both PTEN wild-type and mutant human prostate cancer

Silencing of the IGF1R gene enhances sensitivity to DNA-damaging agents in both PTEN wild-type and mutant human prostate cancer

Akt Down-Regulates ERK1/2 Nuclear Localization and Angiotensin II-induced Cell Proliferation through PEA-15

Contributions of the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways to leukemia

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