Raf-1 regulates Rho signaling and cell migration

Ehrenreiter, Karin; Piazzolla, Daniela; Velamoor, Vanishree; Sobczak, Izabela; Small, J. Victor; Takeda, Junji; Leung, Thomas; Baccarini, Manuela

doi:10.1083/jcb.200409162

Cited by 193 publications

(227 citation statements)

References 66 publications

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“…Thus, reduced expression of Spreds in HCC may contribute to metastasis by upregulating the Rho/ROCK pathway. However, a recent report suggests that Raf-1 physically associates with ROCK and is necessary for Rho/ROCKregulated cell migration (Ehrenreiter et al, 2005). Therefore, Spred may regulate cell motility through the inhibiting the Raf-1 activation in additon to suppression of the Rho/ROKCK activation.…”

Section: Discussionmentioning

confidence: 99%

Spreds, inhibitors of the Ras/ERK signal transduction, are dysregulated in human hepatocellular carcinoma and linked to the malignant phenotype of tumors

et al. 2006

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Aberrant activation of the Ras/Raf-1/extracellular-regulated kinase (ERK) pathway has been shown to be involved in the progression of human hepatocellular carcinoma (HCC). However, the mechanism of dysregulation of ERK activation is poorly understood. Recently, we identified Sprouty-related protein with Ena/vasodilator-stimulated phosphoprotein homology-1 domain (Spred) as a physiological inhibitor of the Ras/Raf-1/ ERK pathway. In this study, we found that the expression levels of Spred-1 and -2 in human HCC tissue were frequently decreased, comparing with those in adjacent non-tumorous tissue. Moreover, Spred expression levels in HCC tissue were inversely correlated with the incidence of tumor invasion and metastasis. Forced expression of Spred-1 inhibited HCC cell proliferation in vitro and in vivo, which was associated with reduced ERK activation. Spred-1 overexpression also reduced the secretion of matrix metalloproteinase-9 (MMP-9) and MMP-2, which play important roles in tumor invasion and metastasis. In addition, Spred-1 inhibited growth factor-mediated HCC cell motility. These data indicate that the reduction of Spred expression in HCC is one of the causes of the acquisition of malignant features. Thus, Spred could be not only a novel prognostic factor but also a new therapeutic target for human HCC.

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Section: Discussionmentioning

confidence: 99%

Spreds, inhibitors of the Ras/ERK signal transduction, are dysregulated in human hepatocellular carcinoma and linked to the malignant phenotype of tumors

et al. 2006

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“…In contrast, B-Raf ablation has been reported to compromise the survival of mature endothelial cells in the embryo proper (18). Although the availability of a conditional knockout has helped establish a MEK-independent role of Raf-1 in apoptosis and migration in vivo (20,21), follow-up work on the effects of B-Raf and MEK-1 ablation has been difficult because of early embryonic lethality. Here, we use conditional mutagenesis to show that the essential role of B-Raf in intrauterine life is restricted to extraembryonic development and that the anomalies observed in the B-Raf knockout (KO) embryos are secondary to placental defects.…”

Section: Raf Kinases From Lower Organisms (Caenorhabditis Elegans Lin-45mentioning

confidence: 99%

Essential role of B-Raf in ERK activation during extraembryonic development

Galabova-Kovacs

Matzen

Piazzolla

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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The kinases of the Raf family have been intensively studied as activators of the mitogen-activated protein kinase kinase͞extra-cellular signal-regulated kinase (ERK) module in regulated and deregulated proliferation. Genetic evidence that Raf is required for ERK activation in vivo has been obtained in lower organisms, which express only one Raf kinase, but was hitherto lacking in mammals, which express more than one Raf kinase. Ablation of the two best studied Raf kinases, B-Raf and Raf-1, is lethal at midgestation in mice, hampering the detailed study of the essential functions of these proteins. Here, we have combined conventional and conditional gene ablation to show that B-Raf is essential for ERK activation and for vascular development in the placenta. B-Rafdeficient placentae show complete absence of phosphorylated ERK and strongly reduced HIF-1␣ and VEGF levels, whereas all these parameters are normal in Raf-1-deficient placentae. In addition, neither ERK phosphorylation nor development are affected in B-raf-deficient embryos that are born alive obtained by epiblastrestricted gene inactivation. The data demonstrate that B-Raf plays a nonredundant role in ERK activation during extraembyronic mammalian development in vivo.T he placenta is the first organ to develop during embryogenesis, and it supports the growth of the developing embryo by mediating the exchange of nutrients and wastes between the fetal and maternal circulatory systems. Placentation includes extensive angiogenesis, and reduced placental vascular development is associated with early embryonic mortality. Genetic studies have demonstrated a crucial role of VEGF, FGF, and their receptors in placental angiogenesis. In addition, the ablation of several signaling molecules operating downstream of receptor tyrosine kinases results in defects in placentation, often at the stage of labyrinth formation (1).The Raf kinases (A-Raf, B-Raf, and Raf-1) relay signals from tyrosine kinase receptors to the mitogen-activated protein kinase kinase (MEK)͞extracellular signal-regulated kinase (ERK) signaling module. Although most of the early work on the activation of the MEK͞ERK module was focused on Raf-1, evidence has accumulated that B-Raf is the main MEK kinase. Raf kinases from lower organisms (Caenorhabditis elegans lin-45 and Drosophila D-Raf ) are more similar to B-Raf than to the other two mammalian Raf kinases. Biochemical studies have indicated that B-Raf is the main MEK kinase found in fibroblast and brain lysates (2-5). Consistently, among the three Raf kinases, B-Raf binds best to MEK (6) and has the highest basal MEK kinase activity, both in vitro (7) and in fibroblasts, when expressed as a conditionally oncogenic form (8). Finally, B-Raf mutations resulting in increased MEK͞ERK activation have been discovered in a broad range of human tumors (9). All these observations hint at B-Raf as the archetypal mammalian MEK kinase, whereas Raf-1 and A-Raf have probably diverged to perform other functions. Growth-factor-stimulated ERK activation is reduced...

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“…This includes the activation of the NF-jB transcription factor, 45,46 the prevention of apoptosis by antagonizing proapoptotic factors such as MST2, the mammalian sterile 20-like kinase, 48 ASK1, the apoptosis signal-regulating kinase 1, 49 and BAD, the BCL-2-antagonist of cell death, 41 and finally the positive regulation of cell migration via the Rho effector kinase Rok-a. 50 The regulation of Raf kinase activity is quite complex, far from being fully understood and beyond the scope of this review. For recent comprehensive reviews, please see Refs.…”

mentioning

confidence: 99%

Raf kinases: Oncogenesis and drug discovery

Schreck

Rapp

2006

Intl Journal of Cancer

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Raf kinase signaling has been thoroughly investigated over the last 20 years. A-Raf, B-Raf and C-Raf, the 3 mammalian members of the Raf family, are involved in a variety of cellular processes such as growth, proliferation, survival, differentiation and transformation. The detection of B-RAF mutations in a wide variety of human cancers, the description of wildtype and mutant B-RAF as tumor antigens in melanoma and the promising outcome of clinical trials evaluating the Raf inhibitor Nexavar 1 (Sorafenib, BAY 43-9006) have sparked a broad interest in the scientific community. After a short historical detour and an introduction into Raf kinase signaling, we are going to discuss here recent outcomes of Raf kinase research with respect to tumor formation and give an overview on current efforts to develop anticancer therapies interfering with aberrant Raf kinase signaling. ' 2006 Wiley-Liss, Inc.Key words: cancer; clinical trials; transformation; drug delivery; signal transduction; mitogenic cascade; Raf kinases Raf kinases: The historyIn 1983, the cloning of the acutely transforming replication-defective mouse type C virus 3611-MSV and characterization of its acquired oncogene was reported. 1 Since 3611-MSV induces rapidly growing f ibrosarcoma in mice, the transduced oncogene was called v-raf, whereas its cellular homologue was named c-raf. 1 Shortly thereafter, Bister and coworkers described the cloning of the avian acute leukemia retrovirus Mil Hill No. 2 (MH2). 2 MH2 was found to carry a second potential oncogene in addition to vmyc, which was termed v-mil, whereas its cellular counterpart was called c-mil. 3 Already a hybridization analysis and the gross comparison of restriction maps of v-raf and v-mil pointed at sequence homologies between these 2 genes. 4 By direct sequencing of both genes it was finally proven that 3611-MSV and MH2 have integrated orthologues of the same gene into their genomes. 5 In the following we are going to use the nomenclature for Raf kinases as proposed in a recent review from Wellbrock et al. 6 In contrast to all other oncogene kinases known at that time, no tyrosine kinase activity was detected in C-Raf. 7 Indeed, it was found that C-Raf is a serine/threonine kinase. 8,9 This and the observation that Raf coexists with the Myc oncogene in retroviruses 10 led to two novel concepts: (i) There is a tyrosine to serine phosphorylation switch as the growth factor signal enters the cell, and (ii) the mechanistic basis for cooperation between nuclear and cytoplasmic oncogenes as well as for signal transduction from cell surface receptors to the nucleus is the phosphorylation of transcription factor class oncogenes such as Myc. 11-13 Growth factor abrogation and oncogene cooperation studies were performed to corroborate this signaling scheme. 14-17 Additional important early findings were (i) the cooperation between Raf and Myc in growth factor independent proliferation, immortalization and tumor induction, 14,18,19 leading to the Raf-Myc balance model, 20 and (ii) the cell lineage-switch ...

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Raf-1 regulates Rho signaling and cell migration

Cited by 193 publications

References 66 publications

Spreds, inhibitors of the Ras/ERK signal transduction, are dysregulated in human hepatocellular carcinoma and linked to the malignant phenotype of tumors

Spreds, inhibitors of the Ras/ERK signal transduction, are dysregulated in human hepatocellular carcinoma and linked to the malignant phenotype of tumors

Essential role of B-Raf in ERK activation during extraembryonic development

Raf kinases: Oncogenesis and drug discovery

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