Guanine nucleotide exchange factors: Activators of the Ras superfamily of proteins

Quilliam, Lawrence A.; Khosravi‐Far, Roya; Huff, Shayne Y.; Der, Channing J.

doi:10.1002/bies.950170507

Cited by 196 publications

(166 citation statements)

References 71 publications

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“…Originally, guanine nucleotide exchange factors (GEFs) were thought to activate Ras exclusively at the PM. [39] Later, it was found that Ras was also switched-on at different endomembranes and by distinct GEFs. For example, Ras is activated by Ras-GRP GEFs at the GC, [40,41] whereas SOS and Ras-GRF GEFs function at the ER.…”

Section: Ras: An Actor On Many Stagesmentioning

confidence: 99%

The Ras‐ERK pathway: Understanding site‐specific signaling provides hope of new anti‐tumor therapies

2010

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Recent discoveries have suggested the concept that intracellular signals are the sum of multiple, site-specified subsignals, rather than single, homogeneous entities. In the context of cancer, searching for compounds that selectively block subsignals essential for tumor progression, but not those regulating ''house-keeping'' functions, could help in producing drugs with reduced side effects compared to compounds that block signaling completely. The Ras-ERK pathway has become a paradigm of how space can differentially shape signaling. Today, we know that Ras proteins are found in different plasma membrane microdomains and endomembranes. At these localizations, Ras is subject to site-specific regulatory mechanisms, distinctively engaging effector pathways and switching-on diverse genetic programs to generate different biological responses. The Ras effector pathway leading to ERKs activation is also under strict, space-related regulatory processes. These findings may open a gate for aiming at the Ras-ERK pathway in a spatially restricted fashion, in our quest for new anti-tumor therapies.

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Section: Ras: An Actor On Many Stagesmentioning

confidence: 99%

The Ras‐ERK pathway: Understanding site‐specific signaling provides hope of new anti‐tumor therapies

2010

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“…11 A number of RasGEFs have been characterized. 4,12 Sos1, and Sos2, for example, are normally localized in the cytosol, but in response to extracellular stimulation, they are recruited to the plasma membrane. Through preliminary analysis of cellular distribution, we carried out subcellular fractionation studies, in which we could precisely show that RasGEF1b is predominantly localized at HMs (Figure 3c; Supplementary Figure 4).…”

Section: Cloning Expression and Subcellular Localization Of Rasgef1mentioning

confidence: 99%

Early endosome localization and activity of RasGEF1b, a toll-like receptor-inducible Ras guanine-nucleotide exchange factor

et al. 2010

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Guanine-nucleotide exchange factors (GEFs) stimulate the intrinsic GDP/GTP exchange activity of Ras and promote the formation of active Ras-GTP, which in turn controls diverse signalling networks important for the regulation of cell proliferation, survival, differentiation, vesicular trafficking, and gene expression. RasGEF1b is a GEF, whose expression is induced in macrophages on stimulation with toll-like receptor (TLR) agonists. Here, we showed that in vitro RasGEF1b expression by macrophages is mostly induced by TLR3 (poly I:C) and TLR4 (lipopolysaccharyde) through the MyD88-independent pathway. In vivo infection with the protozoan parasites Trypanosoma cruzi and Plasmodium chabaudi induced RasGEF1b in an MyD88-, TRIF-, and IFN-g-dependent manner. Ectopically expressed RasGEF1b was found, mostly, in the heavy membrane fraction of HEK 293T, and by confocal microscopy, it was found to be located at early endosomes. Computational modelling of the RasGEF1b-Ras interaction revealed that RasGEF1b interacts with the binding domain site of Ras, a critical region for interacting with GEFs involved in the activation of Ras-Raf-MEK-ERK pathway. More important, RasGEF1b was found to be closely associated with Ras in live cells and to trigger Ras activity. Altogether, these results indicate that on TLR activation, RasGEF1b may trigger Ras-like proteins and regulate specific biological activities described for this subtype of GTPases.

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“…Ras is a point of convergence for diverse extracellular signal-stimulated pathways function as GDP/GTP regulated switches (H-Ras, NRas, K-Ras4A and K-Ras4B) (Barbacid, 1987;Bourne et al, 1990;Boguski and McCormick, 1993;Quilliam et al, 1995). The two forms of K-Ras diverge solely in their COOH-terminal 25 amino acids as a consequence of alternate exon utilization.…”

Section: Introductionmentioning

confidence: 99%

Increasing complexity of Ras signaling

et al. 1998

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The initial discovery that ras genes endowed retroviruses with potent carcinogenic properties and the subsequent determination that mutated ras genes were present in a wide variety of human cancers, prompted a strong suspicion that the growth-promoting actions of mutated Ras proteins contribute to their aberrant regulation of growth stimulatory signaling pathways. In 1993, a remarkable convergence of experimental observations from genetic analyses of Drosophila, S. cerevisiae and C. elegans as well as biochemical and biological studies in mammalian cells came together to de®ne a clear role for Ras in signal transduction. What emerged was an elegant linear signaling pathway where Ras functions as a relay switch that is positioned downstream of cell surface receptor tyrosine kinases and upstream of a cytoplasmic cascade of kinases that included the mitogen-activated protein kinases (MAPKs). Activated MAPKs in turn regulated the activities of nuclear transcription factors. Thus, a signaling cascade where every component between the cell surface and the nucleus was de®ned and conserved in worms,¯ies and man. This was a remarkable achievement in our e orts to appreciate how the aberrant function of Ras proteins may contribute to the malignant growth properties of the cancer cell. However, the identi®cation of this pathway has proven to be just the beginning, rather than the culmination, of our understanding of Ras in signal transduction. Instead, we now appreciate that this simple linear pathway represents but a minor component of a very complex signaling circuitry. Ras signaling has emerged to involve a complex array of signaling pathways, where cross-talk, feedback loops, branch points and multi-component signaling complexes are recurring themes. The simplest concept of a signaling cascade, where each component simply relays the same message to the next, is clearly not the case. In this review, we summarize our current understanding of Ras signal transduction with an emphasis on new complexities associated with the recognition and/or activation of cellular e ectors, and the diverse array of signaling pathways mediated by interaction between Ras and Ras-subfamily proteins with multiple e ectors.

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Guanine nucleotide exchange factors: Activators of the Ras superfamily of proteins

Cited by 196 publications

References 71 publications

The Ras‐ERK pathway: Understanding site‐specific signaling provides hope of new anti‐tumor therapies

The Ras‐ERK pathway: Understanding site‐specific signaling provides hope of new anti‐tumor therapies

Early endosome localization and activity of RasGEF1b, a toll-like receptor-inducible Ras guanine-nucleotide exchange factor

Increasing complexity of Ras signaling

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