Raf gets it together

Cj, Marshall

doi:10.1038/383127a0

Cited by 105 publications

(69 citation statements)

References 11 publications

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“…Such events result in the formation of a specific protein complex leading to the activation of p21 ras GTPase (Denhardt, 1996). The GTP-bound form of p21 ras induces the translocation to the cell membrane and the activation of the serine-threonine protein kinase Raf-1 (Marshall, 1996), which in turn activates a family of dual specificity kinases known as mitogen-activated/extracellularsignal regulated kinase kinase or MEK. MEK is the component of the cascade of phosphorylation events downstream of growth factor receptors, which finally stimulates the extracellular-signalregulated kinases (ERKs) (Crews and Erikson, 1993).…”

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confidence: 99%

“…MEK is the component of the cascade of phosphorylation events downstream of growth factor receptors, which finally stimulates the extracellular-signalregulated kinases (ERKs) (Crews and Erikson, 1993). These enzymes, ERK-1 and ERK-2, belong to a subgroup of MAPKs, a serine/threonine kinases family, which require phosphorylation on both a threonine and a tyrosine residue for their activation and which transmit the mitogenic signal into the nucleus by regulating gene expression through the phosphorylation of a variety of transcription factors (Marshall, 1996). Several attempts have been made to inhibit this pathway whose components are individually capable of inducing malignant transformation when aberrantly controlled (Huang, 1997).…”

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8-Cl-cAMP antagonizes mitogen-activated protein kinase activation and cell growth stimulation induced by epidermal growth factor

et al. 1999

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SummaryThe growth factor-activated mitogenic pathways are often disregulated in tumour cells and, therefore, they can provide specific molecular targets for novel anti-tumour approaches. 8-Chloro-cAMP (8-Cl-cAMP), a synthetic cAMP analogue, is a novel anti-tumour agent that has recently undergone clinical evaluation. We investigated the effects of 8-CI-cAMP on the epidermal growth factor (EGF)/EGF receptor (EGF-R) signalling in human epidermoid cancer KB cells, which are responsive to the mitogenic stimulus of EGF. We found that the growthpromoting activity of EGF was completely abolished when EGF treatment was performed in combination with 8-CI-cAMP. The inhibition of the EGF-induced proliferation by 8-CI-cAMP was paralleled by the blockade of the EGF-stimulated activation of mitogen-activated protein kinases (MAPK), ERK-1 and ERK-2. Conversely, we found an increase of EGF-R expression and EGF-R tyrosine phosphorylation when KB cells were growth inhibited by 8-Cl-cAMP. Moreover, the activity of Raf-1 and MEK-1 protein kinases, the activators upstream MAPK in the phosphorylation cascade induced by EGF, was not modified in 8-Cl-cAMP-treated cells. We concluded that the impairment of KB cell response to EGF, induced by 8-Cl-cAMP, resides in the specific inhibition of MAPK/ERKs activity while the function of the upstream elements in the EGF-R signalling is preserved.

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8-Cl-cAMP antagonizes mitogen-activated protein kinase activation and cell growth stimulation induced by epidermal growth factor

et al. 1999

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“…17 After membrane translocation initiated by Ras, activated Raf proteins associate with cell proliferation in murine and human cytokine-dependent hematopoietic cells, murine NIH-3T3 fibroblasts and A10 smooth muscle cells. 10,30 Src can also activate raf-1 by phosphorylating Raf-1 at S338 and S339. 10 However, in our study, we found that src-transformed CREF cells, CREF-src, remain responsive to mda-5-induced apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…10,30 Src can also activate raf-1 by phosphorylating Raf-1 at S338 and S339. 10 However, in our study, we found that src-transformed CREF cells, CREF-src, remain responsive to mda-5-induced apoptosis. This suggests that other signaling events may also be required to activate the Raf/MEK/ERK pathway.…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, impairment of ras activity hinders raf activation. 6,[9][10][11] Aberrant activation of this pathway is frequently linked with tumor progression and malignancy, which can contribute to the low efficacy of chemotherapy in patients. 6 Mutations leading to constitutive activation of ras have been found in approximately 30% of all human cancers.…”

Section: Introductionmentioning

confidence: 99%

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Activation of Ras/Raf protects cells from melanoma differentiation-associated gene-5-induced apoptosis

Lin

Lebedeva

et al. 2006

Cell Death Differ

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Melanoma differentiation-associated gene-5 (mda-5) was the first molecule identified in nature whose encoded protein embodied the unique structural combination of an N-terminal caspase recruitment domain and a C-terminal DExD/H RNA helicase domain. As suggested by its structure, cumulative evidences documented that ectopic expression of mda-5 leads to growth inhibition and/or apoptosis in various cell lines. However, the signaling pathways involved in mda-5-mediated killing have not been elucidated. In this study, we utilized either genetically modified cloned rat embryo fibroblast cells overexpressing different functionally and structurally distinct oncogenes or human pancreatic and colorectal carcinoma cells containing mutant active ras to resolve the role of the Ras/Raf signaling pathway in mda-5-mediated growth inhibition/apoptosis induction. Rodent and human tumor cells containing constitutively activated Raf/Raf/MEK/ERK pathways were resistant to mda-5-induced killing and this protection was antagonized by intervening in this signal transduction cascade either by directly inhibiting ras activity using an antisense strategy or by targeting ras-downstream factors, such as MEK1/2, with the pharmacological inhibitor PD98059. The present findings provide a further example of potential cross-talk between growth-inhibitory and growth-promoting pathways in which the ultimate balance of these factors defines cellular homeostasis, leading to survival or induction of programmed cell death.

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Mechanisms of inhibition by heparin of PDGF stimulated MAP kinase activation in vascular smooth muscle cells

et al. 1997

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Heparin and heparan are potent inhibitors of vascular smooth muscle cell (VSMC) proliferation. To investigate the mechanisms by which heparin suppresses growth factor stimulated mitogenesis, the present experiments investigated the effects of heparin on platelet-derived growth factor (PDGF) stimulated signal transduction pathways. Heparin treatment substantially inhibited PDGF-BB stimulated rat VSMC growth. Western analysis showed a 30 min PDGF-BB treatment of VSMC induced the tyrosine phosphorylation of multiple protein bands; cotreatment with heparin inhibited mitogen-activated protein (MAP) kinase tyrosine phosphorylation but had little effect on PDGF receptor tyrosine phosphorylation. In-gel kinase assays demonstrated that heparin inhibited PDGF-BB stimulated MAP kinase activity at late (25 min) but not early (10 min) time points. These data indicate that heparin does not inhibit the initial signalling events after PDGF-BB binding but instead acts through an alternate mechanism to inhibit MAP kinase. To investigate if heparin directly stimulates tyrosine phosphatase-mediated suppression of MAP kinase, we treated VSMC with orthovanadate, a tyrosine phosphatase inhibitor. Heparin inhibited MAP kinase tyrosine phosphorylation after orthovanadate treatment, indicating that heparin does not suppress MAP kinase by enlistment of a tyrosine phosphatase. Experiments were performed to investigate signalling pathways upstream of MAP kinase. To determine if protein kinase C (PKC) mediates PDGF-BB, serum, and EGF stimulation of MAP kinase, we treated VSMC overnight with phorbol ester (PMA) to downregulate PKC. Abolition of conventional and novel PKC activity significantly suppressed both serum and PDGF-BB induced MAP kinase activation, indicating protein kinase C is an important mediator for these mitogens. In contrast, downregulation of these PKC isoforms had little effect on EGF stimulation of MAP kinase. As heparin inhibits PDGF and serum but not EGF stimulation of MAP kinase, there data precisely correlate heparin inhibition of MAP kinase with activation through PKC-dependent pathways. Immunoprecipitation analysis found that heparin inhibited serum, PMA, and PDGF but not EGF induced raf-1 phosphorylation. These studies demonstrate that heparin did not block PDGF-BB receptor activation, which initiates the mitogenic signalling cascade. Heparin did inhibit specific postreceptor second messenger signals, such as the late phase activation of MAP kinase, which may be mediated by suppression of PKC-dependent pathways.

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Raf gets it together

Cited by 105 publications

References 11 publications

8-Cl-cAMP antagonizes mitogen-activated protein kinase activation and cell growth stimulation induced by epidermal growth factor

8-Cl-cAMP antagonizes mitogen-activated protein kinase activation and cell growth stimulation induced by epidermal growth factor

Activation of Ras/Raf protects cells from melanoma differentiation-associated gene-5-induced apoptosis

Mechanisms of inhibition by heparin of PDGF stimulated MAP kinase activation in vascular smooth muscle cells

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