• Journal of Integrative Natural Science
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• v.16 no.2
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• pp.69-74
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• 2023

In Dictyostelium , there are 15 Ras subfamilies, including 11 Ras, 3 Rap, 1 Rheb. The Ras proteins are involved in regulating various cell processes as switch proteins. The functions of many Ras proteins have been identified, but some of Ras proteins have not yet been identified. Here, we focused on identifying the roles of RasW among them. To investigate the functions of RasW in cell morphology, cell migration, and development in Dictyostelium , we compared the phenotypes of wild-type cells and rasW null cells. rasW null cells showed a larger, more spread-out morphology and reduced cell motility compared to wild-type cells. There was no significant difference between wild-type cells and rasW null cells during multicellular developmental process. These results suggest that RasW is involved in regulating cell morphology and cell migration in Dictyostelium.

• Archives of Pharmacal Research
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• v.29 no.2
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• pp.113-122
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• 2006

Among the effector molecules connected with the group of cell surface receptors, Ras proteins have essential roles in transducing extracellular signals to diverse intracellular events, by controlling the activities of multiple signaling pathways. For over 20 years since the discovery of Ras proteins, an enormous amount of knowledge has been accumulated as to how the proteins function in overlapping or distinct fashions. The signaling networks they regulate are very complex due to their multiple functions and cross-talks. Much attention has been paid to the pathological role of Ras in tumorigenesis. In particular, human tumors very frequently express Ras proteins constitutively activated by point mutations. Up to date, three members of the Ras family have been identified, namely H-Ras, K-Ras (A and B), and N-Ras. Although these Ras isoforms function in similar ways, many evidences also support the distinct molecular function of each Ras protein. This review summarizes differential functions of Ras and highlights the current view of the distinct signaling network regulated by each Ras for its contribution to the malignant phenotypic conversion of breast epithelial cells. Four issues are addressed in this review: (1) Ras proteins, (2) membrane localization of Ras, (3) effector molecules downstream of Ras, (4) Ras signaling in invasion. In spite of the accumulation of information on the differential functions of Ras, much more remains to be elucidated to understand the Ras-mediated molecular events of malignant phenotypic conversion of cells in a greater detail.

• Journal of Integrative Natural Science
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• v.16 no.2
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• pp.47-51
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• 2023

Ras small GTPases are involved in regulating various cellular signaling pathways including cell migration, proliferation, and differentiation. Ras GTPase subfamily is comprised of 15 proteins; 11 Ras, 3 Rap, and one Rheb related protein. Some Ras proteins, such as RasC and RasG, have been identified for their major functions, but there are proteins whose functions have not been studied yet, such as RasU and RasX. Here, we investigated the roles of RasU in cell motility and development. RasU shows the highest homology with RasX. To investigate the functions of RasU, rasU null cells were used to observe the phenotype. Cells lacking RasU were larger and more spread than wild-type cells. These results indicate that RasU plays a negative role in cell spreading. In addition, we investigated the roles of RasU in cell motility and development of Dictyostelium cells and found that rasU null cells exhibited decreased random migration speed and delayed developmental process. These results suggest that RasU plays an important role in cell motility and development.

• Archives of Pharmacal Research
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• v.21 no.4
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• pp.378-384
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• 1998

The processing pathway of G-proteins and Ras family proteins includes the isoprenylation of the cysteine residue, followed by proteolysis of three terminal residues and .alpha.-carboxyl methyl esterification of the cysteine residue. Farnesylcysteine methyltransferase (FCMT) activity is responsible for the methylation reaction which play a role in the membrane attachment of a variety of cellular proteins. Four kinds of Ras protein (c-Ha-ras, c-N-Ras, c-Ki-Ras, pan-Ras) expression were detected in adenocarcinoma of human tissue by immunohistochemical method, and hematoxylin and eosin staining. The level of Ras protein in human stomach tumor tissues was much higher than in normal and peritumoral regions of the same biopsy samples. The FCMT activities of each cellular fractions were high in mitochondrial fraction followed by microsomal fraction, whole homogenate and cytosolic fraction. The inhibitory effect on FCMT activity on stomach tumor tissue was determined after treatment with 0.25 $\mu\textrm{M}$ of S-adenosyl-$_L$-homocysteine. S-adenosyl-$_L$-homocysteine inhibited FCMT activity from 11.2% to 30.5%. These results suggested that FCMT might be involved in Ras proteins activity.

• Journal of Life Science
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• v.28 no.9
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• pp.1100-1117
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• 2018

The Ras superfamily of small G-proteins acts as a molecular switch on the intracellular signaling pathway. Upon ligand stimulation, inactive GTPases (Ras-GDP) are activated (Ras-GTP) using guanine nucleotide exchange factor (GEF) and transmit signals to their downstream effectors. Following signal transmission, active Ras-GTP become inactive Ras-GDP and cease signaling. However, the intrinsic GTPase activity of Ras proteins is weak, requiring Ras GTPase-activating protein (RasGAP) to efficiently convert RAS-GTP to Ras-GDP. Since deregulation of the Ras pathway is found in nearly 30% of all human cancers, it might be useful to clarify the structural and physiological roles of Ras GTPases. Recently, RasGAP has emerged as a new class of tumor-suppressor protein and a potential therapeutic target for cancer. Therefore, it is important to clarify the physiological roles of the individual GAPs in human diseases. The first RasGAP discovered was RASA1, also known as p120 RasGAP. RASA1 is widely expressed, independent of cell type and tissue distribution. Subsequently, neurofibromatosis type 1 (NF1) was discovered. The remaining GAPs are affiliated with the GAP1 and synaptic GAP (SynGAP) families. There are more than 170 Ras GTPases and 14 Ras GAP members in the human genome. This review focused on the current understanding of Ras GTPase and RasGAP in human diseases, including cancers.

• Molecules and Cells
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• v.20 no.2
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• pp.196-200
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• 2005

The neurofibromatosis type2 (NF2) tumor suppressor gene product, merlin, is structurally related to the ezrin-radixin-moesin (ERM) family of proteins that anchor the actin cytoskeleton to specific membrane proteins and participate in cell signaling. However, the basis of the tumor suppressing activity of merlin is not well understood. Previously, we identified a role of merlin as an inhibitor of the Ras-ERK signaling pathway. Recent studies have suggested that phosphorylation of merlin, as of other ERM proteins, may regulate its function. To determine whether phosphorylation of merlin affects its suppression of Ras-ERK signaling, we generated plasmids expressing full-length merlin with substitutions of serine 518, a potential phosphorylation site. A substitution that mimics constitutive phosphorylation (S518D) abrogated the ability of merlin to suppress effects of the Ras-ERK signaling pathway such as Ras-induced SRE transactivation, Elk-mediated SRE transactivation, Ras-induced ERK phosphorylation and Ras-induced focus formation. On the other hand, an S518A mutant, which mimics nonphosphorylated merlin, acted like wild type merlin. These observations show that mimicking merlin phosphorylation impairs not only growth suppression by merlin but also its inhibitory action on the Ras-ERK signaling pathway.

• Journal of Animal Science and Technology
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• v.64 no.6
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• pp.1024-1034
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• 2022

Identifying effective biomarkers for the diagnosis of male fertility is crucial for improving animal production and treating male infertility in humans. Ras-related proteins (Rab) are associated with morphological and motion kinematic functions in spermatozoa. Moreover, Rab2A, a Rab protein, is a possible male fertility-related biomarker. The present study was designed to identify additional fertility-related biomarkers among the various Rab proteins. First, the expression of Rab proteins (Rab3A, 4, 5, 8A, 9, 14, 25, 27A, and 34A) from 31 duroc boar spermatozoa was measured before and after capacitation; correlation between Rab protein expression and litter size was evaluated by statistical analysis. The results showed that the expression of Rab3A, 4, 5, 8A, 9, and 25 before capacitation and Rab3A, 4, 5, 8A, 9, and 14 after capacitation were negatively correlated with litter size. Moreover, depending on the cutoff values calculated by receiver operating curves, an increase in litter size was observed when evaluating the ability of the Rab proteins to forecast litter size. Therefore, we suggest that Rab proteins may be potential fertility-related biomarkers that could help select superior sires in the livestock industry.

• Korean Journal of Pharmacognosy
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• v.34 no.1 s.132
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• pp.91-99
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• 2003

Ras proteins play an important role in intracellular signal transduction pathways involved in cell growth and the mutated twas genes have been found in thirty percent of human cancers. Ras proteins (H-, K- and N-Ras) are small guanine nucleotide binding proteins that undergo a series of posttranslational modifications including the farnesylation onto cysteine 186 at C-terminal of Ras by farnesyl protein transferase (FPTase). This is a mandatory process for retention of transforming ability. Therefore, inhibitors of FPTase have a promising to be effective antitumor agents. In our screening program for FPTase inhibitors, the methanol extracts of 193 plants were screened for the inhibitory activity against FPTase partially purified from the rat brain. Extracts of 7species plants including Areca catechu, Saururus chinensis, Curcuma longa, Artemisa princeps, Paeonia suffruticosa, Spatholobus suberectus, Cinnamomum cassia, Cinnamomum japonicum inhibited more than 60% of FPTase activity at a concentration of $100\;{\mu}g/ml$.

• Biomedical Science Letters
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• v.15 no.4
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• pp.327-333
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• 2009

Heterotrimeric GTP binding proteins, G-proteins, mediate signal transduction generated by neurotransmitters and hormones. Among G-proteins, Go proteins are the most abundant in brain and classified as a member of Gi family. Ras-like protein in all tissues (Rit), one of the small GTPases, is a member of a Ras superfamily and identified as an important regulator of neuronal differentiation and cell transformation. Recently, we have reported that Rit functioned as a candidate downstream effector for alpha subunit of Go proteins ($Go{\alpha}$) and regulated neurite outgrowth triggered by $Go{\alpha}$ activation. In this study, we showed that the GTPase domain of $Go{\alpha}$ contributed to the direct interaction with Rit. We also demonstrated that $Go{\alpha}$ could lead to an increase of Rit activity suggesting that Rit play a role as a downstream effector of $Go{\alpha}$.

• Tuberculosis and Respiratory Diseases
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• v.51 no.3
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• pp.201-210
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• 2001

Background : Approximately 10-13% of patients with interstitial lung disease(ILD) die of lung cancer, and patients with ILD have been reported to have a 7 fold higher incidence of lung cancer compared to the normal population. Recently, overexpression of the p53 and p21 proteins were observed in the epithelial cells from pathologic specimens of ILD. Overexpression of these proteins may result from chronic or recurrent DNA damage by unknown causes of inflammation. However, these proteins may also contribute to oncogenesis if other genetic alterations such as K-ras are superimposed. Methods : Immunohistochemical stains for p53 and K-ras proteins were performed with pathologic specimens from 38 cases with ILD(M/F : 27/11, mean agea : $54{\pm}10$ years) and from 10 control subjects. Results : The p53 protein was expressed in 21.1% (8/38 ILD cases) and K-ras protein expression was observed in 65.8% (25/38 ILD cases). However, neither p53 nor the K-ras protein staining was observed in the control subjects. Conclusion : A significant proportion of cases with ILD expressed the p53 and K-ras proteins in their bronchial epithelial cells. These proteins may be potentially oncogenic with the addition of further genetic alterations. However, to clarify the significance of these findings, further studies looking for correlations with the incidence of lung cancer and other genetic changes are needed.