The torso receptor tyrosine kinase can activate raf in a ras-independent pathway

Hou, Xianyu; Chou, Tze-Bin; Melnick, Michael; Perrimon, Norbert

doi:10.1016/0092-8674(95)90371-2

Cited by 107 publications

(65 citation statements)

References 57 publications

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“…It is also likely that 14-3-3e has other functions in development in addition to Ras 1 signaling. Embryos derived from females homozygous for loss-offunction 14-3-3e mutations are arrested earlier (data not shown) than those derived from females homozygous for Rasl (Hou et al 1995).…”

Section: Mutations In 14-3-3e Affect Other R a S L -M E D I A T E D Pmentioning

confidence: 96%

14-3-3 epsilon positively regulates Ras-mediated signaling in Drosophila.

Chang¹,

Rubin²

1997

Genes Dev.

132

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We have isolated mutations in the gene encoding a Drosophila 14-3-3e protein as suppressors of the rough eye phenotype caused by the ectopic expression of RAS1 TM. Using a simple loss-of-function 14-3-3c mutation, we show that 14-3-3~ acts to increase the efficiency of RAS1 signaling. The 14-3-3e protein appears to function in multiple RTK pathways, suggesting that it is a general component of RAS1 signaling cascade. Sequence analysis of three dominant-negative alleles defines two regions of 14-3-3~ that participate in RAS1 signaling. We also present evidence that 14-3-3¢ and 14-3-34, two 14-3-3 protein family members, are partially redundant for RAS1 signaling in photoreceptor formation and in animal viability. Our genetic data suggest that 14-3-3e functions downstream of or parallel to RAF, but upstream of nuclear factors in RAS1 signaling.

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Section: Mutations In 14-3-3e Affect Other R a S L -M E D I A T E D Pmentioning

confidence: 96%

14-3-3 epsilon positively regulates Ras-mediated signaling in Drosophila.

Chang¹,

Rubin²

1997

Genes Dev.

132

View full text Add to dashboard Cite

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“…All isoforms share three highly conserved regions (CRs; Figure 1a): the N-terminal CR1 contains the Ras-guanine 5 0 -triphosphate (GTP)-binding domain (RBD), which initiates the interaction with Ras-GTP through a conserved arginine residue (R188 in B-Raf) that is required for the recruitment and activation of Raf at the plasma membrane. Consequently, mutation of this residue prevents Ras/Raf interaction and renders D-Raf, B-Raf and Raf-1 unresponsive to most extracellular signals (Hou et al, 1995;Marais et al, 1997;Brummer et al, 2002). The CR2 contains a negative regulatory serine residue (S259 and S365 in Raf-1 and B-Raf, respectively) that is proposed to serve as a binding site for 14-3-3 proteins, although this has only been confirmed for Raf-1 (Roy et al, 1998;Hekman et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Functional analysis of the regulatory requirements of B-Raf and the B-RafV600E oncoprotein

et al. 2006

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The BRAF V600E mutation is found in approximately 6% of human cancers and mimics the phosphorylation of the kinase domain activation segment. In wild-type B-Raf (B-Raf wt ), activation segment phosphorylation is thought to cooperate with negative charges within the N-region for full activation. In contrast to Raf-1, the N-region of B-Raf is constitutively negatively charged owing to the presence of residues D447/D448 and the phosphorylation of S446. Therefore, it has been suggested that this hallmark predisposes B-Raf for oncogenic activation. In this study, we demonstrate that neutralizing mutations of these residues (in particular S446 and S447), or uncoupling of B-Raf from Ras-guanine 5 0 -triphosphate (GTP), strongly reduce the biological activity of B-Raf in a PC12 cell differentiation assay. We also confirm that S365 is a 14-3-3 binding site, and determine that mutation of this residue rescues the impaired biological activity of B-Raf proteins with a neutralized N-region, suggesting that the N-region opposes a 14-3-3-mediated transition into an inactive conformation. However, in the case of B-Raf V600E , although complete N-region neutralization resulted in a 2.5-fold reduction in kinase activity in vitro, this oncoprotein strongly induced PC12 differentiation or transformation and epithelial-mesenchymal transition of MCF-10A cells regardless of its N-region charge. Furthermore, the biological activity of B-Raf V600E was independent of its ability to bind Ras-GTP. Our analysis identifies important regulatory differences between B-Raf wt and B-Raf V600E and suggests that B-Raf V600E cannot be inhibited by strategies aimed at blocking S446 phosphorylation or Ras activation. Keywords: Ras; 14-3-3 proteins; b-Catenin; E-cadherin; mammary epithelial cells IntroductionThe Ras/Raf/mitogen-activated/extracellular-regulated kinase (MEK)/extracellular signal regulated kinase (ERK) pathway plays a pivotal role in control of proliferation and differentiation and, owing to its role as a gatekeeper of this pathway, Raf appears an attractive therapeutic target (O'Neill and Kolch, 2004;Wilhelm et al., 2004). The Raf-kinase family comprises the A-Raf, B-Raf and Raf-1 isoforms in vertebrates as well as D-Raf and LIN-45 in Drosophila and Caenorhabditis, respectively. B-Raf, the major ERK activator in vertebrates, is required for the maintenance of basal ERK activity and displays the most potent transforming activity (Papin et al., 1998;Brummer et al., 2002;Mercer and Pritchard, 2003). All isoforms share three highly conserved regions (CRs; Figure 1a): the N-terminal CR1 contains the Ras-guanine 5 0 -triphosphate (GTP)-binding domain (RBD), which initiates the interaction with Ras-GTP through a conserved arginine residue (R188 in B-Raf) that is required for the recruitment and activation of Raf at the plasma membrane. Consequently, mutation of this residue prevents Ras/Raf interaction and renders D-Raf, B-Raf and Raf-1 unresponsive to most extracellular signals (Hou et al., 1995;Marais et al., 1997;Brummer et al., 2002). The ...

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“…5G,I). To determine whether ERK signaling was involved in this process, we studied the phenotype of maternalzygotic mutants of Dsor1, which completely lack ERK kinase activity (Hou et al, 1995;Tsuda et al, 1993). These mutants had misplaced and duplicated tracheal pits (Fig.…”

Section: Egfr Mutants Are Defective In Cell Rearrangement and Restricmentioning

confidence: 99%

A wave of EGFR signaling determines cell alignment and intercalation in theDrosophilatracheal placode

Inoue²,

2007

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Invagination of organ placodes converts flat epithelia into three-dimensional organs. Cell tracing in the Drosophila tracheal placode revealed that, in the 30-minute period before invagination, cells enter mitotic quiescence and form short rows that encircle the future invagination site. The cells in the rows align to form a smooth boundary ('boundary smoothing'), accompanied by a transient increase in myosin at the boundary and cell intercalation oriented in parallel with the cellular rows. Cells then undergo apical constriction and invaginate, followed by radially oriented mitosis in the placode. Prior to invagination, ERK MAP kinase is activated in an outward circular wave, with the wave front often correlating with the smoothing cell boundaries. EGFR signaling is required for myosin accumulation and cell boundary smoothing, suggesting its propagation polarizes the planar cell rearrangement in the tracheal placode, and coordinates the timing and position of intrinsic cell internalization activities.

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The torso receptor tyrosine kinase can activate raf in a ras-independent pathway

Cited by 107 publications

References 57 publications

14-3-3 epsilon positively regulates Ras-mediated signaling in Drosophila.

14-3-3 epsilon positively regulates Ras-mediated signaling in Drosophila.

Functional analysis of the regulatory requirements of B-Raf and the B-RafV600E oncoprotein

A wave of EGFR signaling determines cell alignment and intercalation in theDrosophilatracheal placode

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