While K-<i>ras</i> Is Essential for MouseDevelopment, Expression of the K-<i>ras</i> 4A Splice VariantIsDispensable

Plowman, Sarah J.; Williamson, Dominic J.; O’Sullivan, Maureen; Doig, Jennifer; Ritchie, Ann-Marie; Harrison, David J.; Melton, David W.; Arends, Mark J.; Hooper, Martin; Patek, Charles E.

doi:10.1128/mcb.23.24.9245-9250.2003

Cited by 98 publications

(95 citation statements)

References 31 publications

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“…However, it was identified that K-Ras functions as a major regulator of Akt activation in erythroid differentiation [33]. Furthermore, K-Ras is required in development of mouse embryos [34,35], indicating that K-Ras performs specific functions that cannot be carried out by either H-Ras or N-Ras during embryogenesis. Our observations also indicate that knockdown of N-Ras during differentiation induces significantly higher levels of apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Proto-oncogenic H-Ras, K-Ras, and N-Ras are involved in muscle differentiation via phosphatidylinositol 3-kinase

et al. 2010

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Oncogenic H-Ras G12V and its variants have been shown to inhibit muscle differentiation. However, the role of proto-oncogenic Ras (c-Ras) in muscle differentiation remains unclear. The active GTP-bound form of Ras has been known to associate with diverse effectors including Raf, phosphatidylinositol 3-kinase (PI3K), Ral-GDS, and other molecules to transmit downstream signals. We hypothesize that c-Ras may stimulate muscle differentiation by selectively activating PI3K, an important mediator for muscle differentiation. In our experiments, inhibition of c-Ras by farnesyltransferase inhibitors and a dominant negative form of H-Ras (Ras S17N) suppressed muscle differentiation. Consistently, individual knockdown of H-Ras, K-Ras, and N-Ras by siRNAs all blocked muscle differentiation. Interestingly, we found that c-Ras preferentially interacts with PI3K rather than its major binding partner c-Raf, during myogenic differentiation, with total c-Ras activity remaining unchanged. PI3K and its downstream myogenic pathway, the Nox2/NF-κB/inducible nitric oxide synthase (iNOS) pathway, were found to be suppressed by inhibition of c-Ras activity during differentiation. Furthermore, expression of a constitutively active form of PI3K completely rescued the differentiation block and reactivated the Nox2/NF-κB/iNOS pathway in c-Ras-inhibited cells. On the basis of our results, we conclude that contrary to oncogenic Ras, proto-oncogenic H-Ras, K-Ras, and N-Ras are directly involved in the promotion of muscle differentiation via PI3K and its downstream signaling pathways. In addition, PI3K pathway activation is associated with a concurrent suppression of the otherwise predominantly activated Raf/ Mek/Erk pathway.

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Section: Discussionmentioning

confidence: 99%

Proto-oncogenic H-Ras, K-Ras, and N-Ras are involved in muscle differentiation via phosphatidylinositol 3-kinase

et al. 2010

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“…GAPs stimulate the intrinsic GTPase activity of Ras 10,000-fold, oncogenic Ras mutations interfere with the ability of GAPs to interact with Ras producing constitutively active Ras proteins. In the same way that multiple GEFs have been identified, 8 GAPs have been characterised providing a range of possibilities for initiating down-regulation of Ras signalling.…”

Section: Introductionmentioning

confidence: 99%

Ras proteins: paradigms for compartmentalised and isoform-specific signalling

Omerovic

Laude

Prior

2007

Cell. Mol. Life Sci.

116

122

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Ras GTPases mediate a wide variety of cellular processes by converting a multitude of extracellular stimuli into specific biological responses including proliferation, differentiation and survival. In mammalian cells, three ras genes encode four Ras isoforms (H-Ras, K-Ras4A, KRas4B and N-Ras) that are highly homologous but functionally distinct. Differences between the isoforms, including their post-translational modifications and intracellular sorting, mean that Ras has emerged as an important model system of compartmentalised signalling and membrane biology. Ras isoforms in different subcellular locations are proposed to recruit distinct upstream and downstream accessory proteins and activate multiple signalling pathways. Here, we summarise data relating to isoform specific signalling, its role in disease and the mechanisms promoting compartmentalised signalling. Further understanding of this field will reveal the role of Ras signalling in development, cellular homeostasis and cancers and may suggest new therapeutic approaches.

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“…[1][2][3] In addition, knockout mice revealed essential roles for K-Ras in development, while H-and N-Ras appeared dispensible for mouse embryogenesis. [16][17][18][19] Along these lines, defects in human development have recently been associated with Ras isoform-specific functions. [19][20][21] The different magnitude of oncogenic Ras isoform signaling further supports signal specificity of Ras isoforms.…”

Section: Functional Differences Of Ras Isoforms and Differential Gap mentioning

confidence: 99%

Differential Regulation of RasGAPs in Cancer

et al. 2011

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Ever since their discovery as cellular counterparts of viral oncogenes more than 25 years ago, much progress has been made in understanding the complex networks of signal transduction pathways activated by oncogenic Ras mutations in human cancers. The activity of Ras is regulated by nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs), and much emphasis has been put into the biochemical and structural analysis of the Ras/GAP complex. The mechanisms by which GAPs catalyze Ras-GTP hydrolysis have been clarified and revealed that oncogenic Ras mutations confer resistance to GAPs and remain constitutively active. However, it is yet unclear how cells coordinate the large and divergent GAP protein family to promote Ras inactivation and ensure a certain biological response. Different domain arrangements in GAPs to create differential protein-protein and protein-lipid interactions are probably key factors determining the inactivation of the 3 Ras isoforms H-, K-, and N-Ras and their effector pathways. In recent years, in vitro as well as cell-and animal-based studies examining GAP activity, localization, interaction partners, and expression profiles have provided further insights into Ras inactivation and revealed characteristics of several GAPs to exert specific and distinct functions. This review aims to summarize knowledge on the cell biology of RasGAP proteins that potentially contributes to differential regulation of spatiotemporal Ras signaling.

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While K-ras Is Essential for MouseDevelopment, Expression of the K-ras 4A Splice VariantIsDispensable

Cited by 98 publications

References 31 publications

Proto-oncogenic H-Ras, K-Ras, and N-Ras are involved in muscle differentiation via phosphatidylinositol 3-kinase

Proto-oncogenic H-Ras, K-Ras, and N-Ras are involved in muscle differentiation via phosphatidylinositol 3-kinase

Ras proteins: paradigms for compartmentalised and isoform-specific signalling

Differential Regulation of RasGAPs in Cancer

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