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Functions of Oncogene and Proto-Oncogene Protein Products
Published in Pimentel Enrique, Oncogenes, 2020
Another oncogene, ets, shows significant primary sequence homology with the predicted translational products of two genes (CDC4 and CDC36) involved in the control of cell proliferation in yeast.93 Sequences related to ras genes are also present in yeast,59,60 which suggests that the mechanisms involved in the control of cell division in yeast and vertebrates may be related or similar.93 There are two genes, termed RAS-1 and RAS-2, contained in the yeast genome which are functionally homologous to mammalian ras genes, being involved in the control of adenylate cyclase, and the RAS2 protein exhibit guanine nucleotide binding activity similar to that possessed by mammalian p2lc-ras.94-96 Yeast cells that lack functional RAS-1 and RAS-2 genes are ordinarily nonviable but may remain viable if they carry a c-W-ras gene of mammalian origin.97 A p21ra*-related protein is also present in Dictyostelium discoideum, where it is developmentally regulated.98
Properties of CDC25-Like Proteins
Published in Juan Carlos Lacal, Frank McCormick, The ras Superfamily of GTPases, 2017
Andrea Parmeggiani, Michel-Yves Mistou, Eric Jacquet, Patrick Poullet, Jean-Bernard Créchet
In Saccharomyces cerevisiae the cell division cycle gene CDC25 is a fundamental element of the RAS/adenylate cyclase pathway which controls the production of cAMP, an internal signal for the onset of cell division.1-5 Temperature-sensitive mutations of this gene lead to a growth arrest in the Gl phase. Several lines of evidence indicate that the CDC25 gene product, which is probably involved in monitoring environmental signals, acts upstream of the RAS proteins which regulate adenylate cyclase activity.6,7 The two homologous proteins RASI and RAS2, which share considerable similarities with mammalian ras proteins, are GTPases and, as for all members of this class of proteins, their function is controlled by GTP and GDP, which respectively, induce the active and the inactive conformation.8-11 Because of the tight binding of GDP and GTP, the key steps of the RAS-guanine nucleotide cycle are the dissociation of the RAS-GDP complex, which conditions the regeneration of the active complex RAS-GTP, and the hydrolysis of GTP which turns off the active state of RAS. The very low rates of the intrinsic GDP to GTP exchange and GTPase of RAS imply the existence of effectors to assure a rapid transient response to the extracellular stimuli which lead to cAMP production.12-14 In S. cerevisiae the product of IRA2 (and probably also that of IRAI) corresponds functionally to mammalian GTPase-activating protein (GAP).15 Concerning the GDP to GTP exchange of RAS, there is enough evidence that the CDC25 gene product is a regulator of this reaction. This was first suggested by the observation that dominant mutations of RAS2 increasing the level of the RAS2-GTP complex can bypass the growth arrest caused by thermosensitive cdc25 mutations.4,5,16 The use of reconstituted systems for cAMP production in vitro has further supported the involvement of the CDC25 gene product in the nucleotide exchange of RAS proteins.17 It has been reported that partially purified CDC25-β-galactosidase fusion products or extracts from yeast cells with overexpressed CDC25 gene can accelerate the RAS2-GDP dissociation in vitro.18
RAP GTPases and platelet integrin signaling
Published in Platelets, 2019
Lucia Stefanini, Wolfgang Bergmeier
In contrast, the founding members of the RAS superfamily are either undetectable (H-RAS, R-RAS2) or present in very limited amounts in platelets (K-RAS, N-RAS, R-RAS) [1–4] (Table I). Like RAP, RAS GTPases can be activated in vitro upon platelet stimulation with various agonists [14, 15]. However, it is unclear whether they play a role in platelet biology, especially as their activation is not coupled to the activation of ERK MAP kinase [15], a common downstream target of RAS in other cells. Notably, guanine nucleotide exchange factors (GEFs), the enzymes that catalyze GTP loading (activation), can discriminate between RAS and RAP proteins [6, 16], and high-throughput profiling studies [1–4] showed that the most highly expressed GEFs present in platelets (Table I) preferentially activate RAP over RAS GTPases.
Silencing thioredoxin1 exacerbates damage of astrocytes exposed to OGD/R by aggravating apoptosis through the Actin–Ras2–cAMP–PKA pathway
Published in International Journal of Neuroscience, 2018
Kunting Zhu, Qi He, Lingyu Li, Yong Zhao, Jing Zhao
Immunoprecipitation was performed to explore the potential combination of Trx1 and actin. In our study, we found that OGD/R stimulus significantly decreased the combination of actin and Trx1 compared to the control group and that shRNA treatment under OGD/R condition further decreased the combination (Figure 4(A–D)). Therefore, Trx1 was identified as a binding partner for actin. Next, we determined the protein expressions of Ras2, cAMP, and PKA using western blot (Figure 5(A–D)). Compared with the control group, a significant increase in the expressions of Ras2, cAMP, and PKA was found in the OGD/R group (*P < 0.05). Importantly, compared with the OGD/R group, an obvious increase in these protein expressions was also found in the OGD/R-shRNA group (<0.05). Meanwhile, we measured the mRNA levels of Ras2 and PKA using qPCR (Figure 5(E,F)), and the results were consistent with those in western blot (*P < 0.05, #P < 0.05). Overall, these results suggest that the Actin–Ras2–cAMP–PKA pathway plays an important role in OGD/R-induced apoptosis.
Small GTPases in platelet membrane trafficking
Published in Platelets, 2019
Tony G. Walsh, Yong Li, Andreas Wersäll, Alastair W. Poole
The Ras sarcoma (Ras) GTPases are the second largest family of the Ras superfamily containing 36 members classically associated with cell proliferation, differentiation and survival, while approximately 30% of all human cancers contain Ras activating mutations [71]. Numerous Ras members are expressed in platelets (Figure 3) and early studies demonstrated that Ras could be activated following platelet stimulation [72,73]. However this did not result in the classical activation of the MAP kinase ERK, as is the case in nucleated cells and the relevance of K-, N- and R-Ras GTPases in platelet function remains unclear. Notably, mutations in four different genes associated with Ras signalling, including K-RAS, are linked to the autosomal dominant disorder, Noonan syndrome (NS) [74]. These patients present with a bleeding diathesis and defects in platelet function have been reported, although K-RAS mutations only account for < 2% of NS patients [75,76]. Interestingly, a recent publication by Janapati et al. demonstrated a role for R-Ras2 (TC21) in GPVI-induced integrin activation, granule secretion and thrombus formation, which acted upstream of Rap1B [77]. Rap1 (A and B) are the most abundantly expressed Ras members in platelets and critical roles with respect to platelet integrin activation and adhesiveness have been established, while roles for the much lower expressed Rap2 (A, B and C) members remain elusive. Zhang and colleagues demonstrated that Rap1B is also important for granule (α- and dense) secretion, although the underlying mechanism is not known [78]. For further information on Rap signalling in platelets, we refer the reader to a recent review by Stefanini and Bergmeier [79].