Signaling Through RAS-RAF-MEK-ERK: from Basics to Bedside

Zebisch, Armin; Czernilofsky, Armin P.; Kéri, Gÿorgý; Smigelskaite, Julja; Sill, Heinz; Troppmair, Jakob

doi:10.2174/092986707780059670

Cited by 105 publications

(87 citation statements)

References 139 publications

(224 reference statements)

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“…5,33 In this study, we have identified loss of the C-RAF --MEK inhibitor RKIP as an additional frequent molecular event affecting this crucial signaling pathway in AML. So far, several lines of evidence have established RKIP as a metastasis suppressor in solid neoplasms.…”

Section: Discussionmentioning

confidence: 89%

“…Transmission of signals from the cell surface to intracellular effectors within this pathway is mediated by RAS-induced activation of a three-tiered kinase cascade comprising RAF, MEK and MAPK/ERK. 5,6 Oncogenic mutations affecting this pathway are frequently observed in human cancers with NRAS or KRAS mutations occurring in about 20% of AML patients. 5 Constitutive RAS-MAPK/ERK signaling is also initiated by somatic mutations in genes encoding the upstream FLT3 and c-Kit receptor tyrosine kinases in an additional 25 --40% of AML cases.…”

Section: Introductionmentioning

confidence: 99%

“…5,6 Oncogenic mutations affecting this pathway are frequently observed in human cancers with NRAS or KRAS mutations occurring in about 20% of AML patients. 5 Constitutive RAS-MAPK/ERK signaling is also initiated by somatic mutations in genes encoding the upstream FLT3 and c-Kit receptor tyrosine kinases in an additional 25 --40% of AML cases. 3,7,8 RAF kinase inhibitor protein (RKIP)---also known as PEBP1, phosphatidylethanolamine binding protein 1---has been identified as a negative regulator of the RAS-MAPK/ERK signaling cascade.…”

Section: Introductionmentioning

confidence: 99%

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Frequent loss of RAF kinase inhibitor protein expression in acute myeloid leukemia

et al. 2012

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RAF kinase inhibitor protein (RKIP) is a negative regulator of the RAS-mitogen-activated protein kinase/extracellular signalregulated kinase signaling cascade. We investigated its role in acute myeloid leukemia (AML), an aggressive malignancy arising from hematopoietic stem and progenitor cells (HSPCs). Western blot analysis revealed loss of RKIP expression in 19/103 (18%) primary AML samples and 4/17 (24%) AML cell lines but not in 10 CD34 þ HSPC specimens. In in-vitro experiments with myeloid cell lines, RKIP overexpression inhibited cellular proliferation and colony formation in soft agar. Analysis of two cohorts with 103 and 285 AML patients, respectively, established a correlation of decreased RKIP expression with monocytic phenotypes. RKIP loss was associated with RAS mutations and in transformation assays, RKIP decreased the oncogenic potential of mutant RAS. Loss of RKIP further related to a significantly longer relapse-free survival and overall survival in uni-and multivariate analyses. Our data show that RKIP is frequently lost in AML and correlates with monocytic phenotypes and mutations in RAS. RKIP inhibits proliferation and transformation of myeloid cells and decreases transformation induced by mutant RAS. Finally, loss of RKIP seems to be a favorable prognostic parameter in patients with AML.

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Section: Discussionmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Frequent loss of RAF kinase inhibitor protein expression in acute myeloid leukemia

et al. 2012

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“…Their activation is a complex process involving interactions with proteins and lipids as well as phosphorylation and requires the assembly of signalosomes, which, along with the core components of the signaling cascade, contain accessory molecules required for modulation, compartmentalization, and specificity (1)(2)(3). RAF kinases are upstream of a three-tiered mitogen-activated protein kinase (MAPK) cascade comprising the dual-specificity Ser/Thr MAPK kinases (MAP2K) MEK1/2 and their substrates ERK1/2, which are required for most reported RAF effects (4,5). Several proteins have been described, which may be important for RAF activation and signaling under specific conditions at distinct cellular sites.…”

Section: Introductionmentioning

confidence: 99%

Isolation of a Novel Thioflavin S–Derived Compound That Inhibits BAG-1–Mediated Protein Interactions and Targets BRAF Inhibitor–Resistant Cell Lines

Enthammer

Papadakis

Gachet

et al. 2013

Molecular Cancer Therapeutics

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Protein-protein interactions mediated through the C-terminal Bcl-2-associated athanogene (BAG) domain of BAG-1 are critical for cell survival and proliferation. Thioflavin S (NSC71948)-a mixture of compounds resulting from the methylation and sulfonation of primulin base-has been shown to dosedependently inhibit the interaction between BAG-1 and Hsc70 in vitro. In human breast cancer cell lines, with high BAG-1 expression levels, Thioflavin S reduces the binding of BAG-1 to Hsc70, Hsp70, or CRAF and decreases proliferation and viability. Here, we report the development of a protocol for the purification and isolation of biologically active constituents of Thioflavin S and the characterization of the novel compound Thio-2. Thio-2 blocked the growth of several transformed cell lines, but had much weaker effects on untransformed cells. Thio-2 also inhibited the proliferation of melanoma cell lines that had become resistant to treatment with PLX4032, an inhibitor of mutant BRAF. In transformed cells, Thio-2 interfered with intracellular signaling at the level of RAF, but had no effect on the activation of AKT. Thio-2 decreased binding of BAG-1 to Hsc70 and to a lesser extent BRAF in vitro and in vivo, suggesting a possible mechanism of action. Given that tumors frequently develop resistance to kinase inhibitors during treatment, Thio-2 and related compounds may offer promising alternative strategies to currently available therapies.

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“…Ras receives extracellular signals from membrane receptors and recruits various effectors to the plasma membrane [11]. Raf, an important Ras effector, then phosphorylates Mek, which in turn phosphorylates the Erk/MAPK kinases that relay information to multiple cytoplasmic and nuclear effector targets [12].…”

Section: Introductionmentioning

confidence: 99%

N‐Ras or K‐Ras inhibition increases the number and enhances the function of Foxp3 regulatory T cells

et al. 2008

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Naturally occurring regulatory T cells (Treg) driven by their transcriptional controller Foxp3 are compromised in immune-mediated disorders and confer protection when adoptively transferred. We examined the Ras-inhibitory effect on functional determinants of Treg in vivo and in vitro. Ras was inhibited in Jurkat T cells by transfection with a dominantnegative form of Ras, or by shRNA for N-Ras, K-Ras, and H-Ras, or by farnesylthiosalycylic acid, a small-molecule inhibitor. Except for H-Ras transduction with shRNA, each inhibitory mode increased expression of Foxp3 and nuclear factor of activated T cell proteins, and surface expression of CD25. Ras inhibition in PBMC and spleen-derived lymphocytes reproduced these findings. The heightened Foxp3 expression reflected both increased basal cellular protein and peripheral conversion of non-Treg to Treg. Ras inhibition enhanced Treg-induced suppression; thus, when adoptively transferred to mice, Ras-inhibited Treg reduced the incidence of diabetes. Inhibition of Foxp3 by respective siRNA reversed the enhancement. Thus, inhibition of the N-or K-Ras isoform triggers an anti-inflammatory effect by up-regulating, via Foxp3 elevation, the numbers and functional suppressive properties of Treg.

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Signaling Through RAS-RAF-MEK-ERK: from Basics to Bedside

Cited by 105 publications

References 139 publications

Frequent loss of RAF kinase inhibitor protein expression in acute myeloid leukemia

Frequent loss of RAF kinase inhibitor protein expression in acute myeloid leukemia

Isolation of a Novel Thioflavin S–Derived Compound That Inhibits BAG-1–Mediated Protein Interactions and Targets BRAF Inhibitor–Resistant Cell Lines

N‐Ras or K‐Ras inhibition increases the number and enhances the function of Foxp3 regulatory T cells

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