Sensitivity of wild type and mutant ras alleles to Ras specific exchange factors: Identification of factor specific requirements

Nielsen, Klaus; Gredsted, Lars; Broach, James R.; Willumsen, Berthe M.

doi:10.1038/sj.onc.1204306

Cited by 9 publications

(10 citation statements)

References 61 publications

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“…This observation adds to the argument that Ras-GRF1 and Sos1 use somewhat different mechanisms to promote guanine nucleotide exchange on Ha-Ras. A similar conclusion was reached recently in mutagenic studies of GTPases that investigated the basis for signaling specificity differences between Ras-GRF1 (Cdc25 Mm ) and Rap-GEF C3G (44) and Ras-GRP (45).…”

Section: Sos1 and Ras-grf Signaling Specificity Differencessupporting

confidence: 79%

Basis for Signaling Specificity Difference between Sos and Ras-GRF Guanine Nucleotide Exchange Factors

Tian

Feig

2001

Journal of Biological Chemistry

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Sos and Ras-GRF are two families of guanine nucleotide exchange factors that activate Ras proteins in cells. Sos proteins are ubiquitously expressed and are activated in response to cell-surface tyrosine kinase stimulation. In contrast, Ras-GRF proteins are expressed primarily in central nervous system neurons and are activated by calcium/calmodulin binding and by phosphorylation. Although both Sos1 and Ras-GRF1 activate the Ras proteins Ha-Ras, N-Ras, and Ki-Ras, only Ras-GRF1 also activates the functionally distinct R-Ras GTPase. In this study, we determined which amino acid sequences in these exchange factors and their target GTPases are responsible for this signaling specificity difference. Analysis of chimeras and individual amino acid exchanges between Sos1 and Ras-GRF1 revealed that the critical amino acids reside within an 11-amino acid segment of their catalytic domains between the second and third structurally conserved regions (amino acids (aa) 828 -838 in Sos1 and 1057-1067 in Ras-GRF1) of Ras guanine nucleotide exchange factors. In Sos1, this segment is in helix B, which is known to interact with the switch 2 region of Ha-Ras. Interestingly, a similar analysis of Ha-Ras and R-Ras chimeras did not identify the switch 2 region of Ha-Ras as encoding specificity. Instead, we found a more distal protein segment, helix 3 (aa 91-103 in Ha-Ras and 117-129 in R-Ras), which interacts instead primarily with helix K (aa 1002-1016) of Sos1. These findings suggest that specificity derives from the fact that R-Ras-specific amino acids in the region analogous to Ha-Ras helix 3 prevent a functional interaction with Sos1 indirectly, possibly by preventing an appropriate association of its switch 2 region with helix B of Sos1. Although previous studies have shown that helix B of Sos1 and helix 3 of Ha-Ras are involved in promoting nucleotide exchange on Ras proteins, this study highlights the importance of these regions in establishing signaling specificity.

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Section: Sos1 and Ras-grf Signaling Specificity Differencessupporting

confidence: 79%

Basis for Signaling Specificity Difference between Sos and Ras-GRF Guanine Nucleotide Exchange Factors

Tian

Feig

2001

Journal of Biological Chemistry

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“…This region of the protein is highly conserved and could presumably affect its interaction with one or more of the GEFs or one of the numerous downstream effectors or both. While mutations in residues such as D69 or R73 of H-Ras have an impact on the association with GEFs, CDC25 (Segal et al 1995), SOS, or GRP (Nielsen et al 2001), the changes T74I and T74A have been shown not to be critical for interaction with any of these exchange factors (Segal et al 1995;Nielsen et al 2001). Interestingly genetic data suggest that mutations in T74 may be important for proper activation of adenylyl cyclase in yeast (Segal et al 1995), although this seems to vary with the assay conditions (Nielsen et al 2001).…”

Section: Discussionmentioning

confidence: 99%

“…While mutations in residues such as D69 or R73 of H-Ras have an impact on the association with GEFs, CDC25 (Segal et al 1995), SOS, or GRP (Nielsen et al 2001), the changes T74I and T74A have been shown not to be critical for interaction with any of these exchange factors (Segal et al 1995;Nielsen et al 2001). Interestingly genetic data suggest that mutations in T74 may be important for proper activation of adenylyl cyclase in yeast (Segal et al 1995), although this seems to vary with the assay conditions (Nielsen et al 2001). In addition, a single recessive substitution in the position N81 of yeast Ras2 (equivalent to H-Ras T74) does not significantly change the Ras-GEF interaction, although it affects adenylyl cyclase activity as inferred from complementation assays (Hermann-Le Denmat and Jacquet 1997).…”

Section: Discussionmentioning

confidence: 99%

The band mutation in Neurospora crassa is a dominant allele of ras-1 implicating RAS signaling in circadian output

Belden¹,

Larrondo²,

Froehlich³

et al. 2007

Genes Dev.

163

155

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band, an allele enabling clear visualization of circadianly regulated spore formation (conidial banding), has remained an integral tool in the study of circadian rhythms for 40 years. bd was mapped using single-nucleotide polymorphisms (SNPs), cloned, and determined to be a T79I point mutation in ras-1. [Keywords: Circadian; output; band; ras-1; ROS] Supplemental material is available at http://www.genesdev.org. Alterations in light-

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“…The viral H-Ras (Nielsen et al, 2007), N-Ras and K-Ras have been described elsewhere (Nielsen et al, 2001). ATF2 was cloned into pBabe (pB)-Neo at BamHI-SalI site.…”

Section: Plasmidsmentioning

confidence: 99%

Identification of a c-Jun N-terminal kinase-2-dependent signal amplification cascade that regulates c-Myc levels in ras transformation

et al. 2011

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Ras is one of the most frequently activated oncogenes in cancer. Two mitogen-activated protein kinases (MAPKs) are important for ras transformation: extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase 2 (JNK2). Here we present a downstream signal amplification cascade that is critical for ras transformation in murine embryonic fibroblasts. This cascade is coordinated by ERK and JNK2 MAPKs, whose Rasmediated activation leads to the enhanced levels of three oncogenic transcription factors, namely, c-Myc, activating transcription factor 2 (ATF2) and ATF3, all of which are essential for ras transformation. Previous studies show that ERK-mediated serine 62 phosphorylation protects c-Myc from proteasomal degradation. ERK is, however, not alone sufficient to stabilize c-Myc but requires the cooperation of cancerous inhibitor of protein phosphatase 2A (CIP2A), an oncogene that counteracts protein phosphatase 2A-mediated dephosphorylation of c-Myc. Here we show that JNK2 regulates Cip2a transcription via ATF2. ATF2 and c-Myc cooperate to activate the transcription of ATF3. Remarkably, not only ectopic JNK2, but also ectopic ATF2, CIP2A, c-Myc and ATF3 are sufficient to rescue the defective ras transformation of JNK2-deficient cells. Thus, these data identify the key signal converging point of JNK2 and ERK pathways and underline the central role of CIP2A in ras transformation.

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Sensitivity of wild type and mutant ras alleles to Ras specific exchange factors: Identification of factor specific requirements

Cited by 9 publications

References 61 publications

Basis for Signaling Specificity Difference between Sos and Ras-GRF Guanine Nucleotide Exchange Factors

Basis for Signaling Specificity Difference between Sos and Ras-GRF Guanine Nucleotide Exchange Factors

The band mutation in Neurospora crassa is a dominant allele of ras-1 implicating RAS signaling in circadian output

Identification of a c-Jun N-terminal kinase-2-dependent signal amplification cascade that regulates c-Myc levels in ras transformation

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