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Articles by K Kato
Total Records ( 7 ) for K Kato
  D Hu , Y Kamiya , K Totani , D Kamiya , N Kawasaki , D Yamaguchi , I Matsuo , N Matsumoto , Y Ito , K Kato and K. Yamamoto
 

Glucosidase II (GII) is a glycan-processing enzyme that trims two 1,3-linked glucose residues from N-glycan on newly synthesized glycoproteins. Trimming of the first 1,3-linked glucose from Glc2Man9GlcNAc2 (G2M9) is important for a glycoprotein to interact with calnexin/calreticulin (CNX/CRT), and cleavage of the innermost glucose from Glc1Man9GlcNAc2 (G1M9) sets glycoproteins free from the CNX/CRT cycle and allows them to proceed to the Golgi apparatus. GII is a heterodimeric complex consisting of a catalytic subunit (GII) and a tightly associated β subunit (GIIβ) that contains a mannose 6-phosphate receptor homology (MRH) domain. A recent study has suggested a possible involvement of the MRH domain of GIIβ (GIIβ-MRH) in the glucose trimming process via its putative sugar-binding activity. However, it remains unknown whether GIIβ-MRH possesses sugar-binding activity and, if so, what role this activity plays in the function of GII. Here, we demonstrate that human GIIβ-MRH binds to high-mannose-type glycans. Frontal affinity chromatography revealed that GIIβ-MRH binds most strongly to the glycans with the 1,2-linked mannobiose structure. GII with the mutant GIIβ that lost the sugar-binding activity of GIIβ-MRH hydrolyzes p-nitrophenyl--glucopyranoside, but the capacity to remove glucose residues from G1M9 and G2M9 is significantly decreased. Our results clearly demonstrate the capacity of the GIIβ-MRH to bind high-mannose-type glycans and its importance in efficient glucose trimming of N-glycans.

  N Hosokawa , L. O Tremblay , B Sleno , Y Kamiya , I Wada , K Nagata , K Kato and A. Herscovics
 

Glycoprotein folding and degradation in the endoplasmic reticulum (ER) is mediated by the ER quality control system. Mannose trimming plays an important role by forming specific N-glycans that permit the recognition and sorting of terminally misfolded conformers for ERAD (ER-associated degradation). The EDEM (ER degradation enhancing -mannosidase-like protein) subgroup of proteins belonging to the Class I 1,2-mannosidase family (glycosylhydrolase family 47) has been shown to enhance ERAD. We recently reported that overexpression of EDEM3 enhances glycoprotein ERAD with a concomitant increase in mannose-trimming activity in vivo. Herein, we report that overexpression of EDEM1 produces Glc1Man8GlcNAc2 isomer C on terminally misfolded null Hong Kong 1-antitrypsin (NHK) in vivo. Levels of this isomer increased throughout the chase period and comprised approximately 10% of the [3H]mannose-labeled N-glycans on NHK after a 3-h chase. Furthermore, overexpression of EDEM1 E220Q containing a mutation in a conserved catalytic residue essential for 1,2-mannosidase activity did not yield detectable levels of Glc1Man8GlcNAc2 isomer C. Yet, the same extent of NHK ERAD-enhancement was observed in both EDEM1 and EDEM1 E220Q overexpressing cells. This can be attributed to both wild-type and mutant EDEM1 inhibiting aberrant NHK dimer formation. We further analyzed the N-glycan profile of total cellular glycoproteins from HepG2 cells stably overexpressing EDEM1 and found that the relative amount of Man7GlcNAc2 isomer A, which lacks the terminal B and C branch mannoses, was increased compared to parental HepG2 cells. Based on this observation, we conclude that EDEM1 activity trims mannose from the C branch of N-glycans in vivo.

  H Yagi , M Yanagisawa , K Kato and R. K. Yu
 

Stage-specific embryonic antigen-1 (SSEA-1) is a well-known carbohydrate antigenic epitope of undifferentiated cells, including neural stem cells (NSCs). However, the exact nature of the carrier proteins has not been fully characterized. Using proteomics analyses, we herein report that a lysosomal protein, LAMP-1, is a major carrier protein of SSEA-1 in NSCs, despite the common belief that SSEA-1 is mainly expressed on the cell surface and constitutes a component of the extracellular matrix. Furthermore, we found that SSEA-1 on LAMP-1 is completely ablated in differentiated cells derived from NSCs. Our finding raises the possibility that the expression of SSEA-1-positive LAMP-1 is associated with the "stemness" of NSCs.

  N. T Okita , Y Yamada , D Takahari , Y Hirashima , J Matsubara , K Kato , T Hamaguchi , K Shirao , Y Shimada , H Taniguchi and T. Shimoda
  Objective

Vascular endothelial growth factor (VEGF) and its receptors VEGF-R1, -R2 and -R3 play important roles in tumor angiogenesis and are associated with poor prognosis in several solid tumors. However, their functional significance remains unclarified. Here, we investigated the associations between the expression of these receptors and the clinical outcomes of colorectal cancer (CRC) patients.

Methods

An immunohistochemical approach was used to detect VEGF-R1, -R2 and -R3 expression in 91 CRC patients who underwent surgery and received chemotherapy at the National Cancer Center Hospital. Statistical analysis was performed to determine the prognostic significance of these biomarkers.

Results

Immunoreactivity for VEGF-R2 and -R3 was localized in microvessels and that for VEGF-R1 in cancer cells and stromal microvessels. VEGF-R1 staining in cancer cells (>10% staining) was found in 84 patients (92%) and in stromal vessels in 75 patients (82%). VEGF-R2 staining in tumor vessels (>10% staining) was found in 84 patients (92%), whereas VEGF-R3 staining was found in 85 patients (93%). Strong positive staining (>60% staining) of VEGF-R1 in tumor cells, and VEGF-R1, -R2 and -R3 in vessels was identified in 58 (64%), 33 (36%), 52 (57%) and 60 (66%) patients, respectively. Univariate analysis revealed that VEGF-R1 strong positive staining correlated with shorter post-operative survival in patients with Stage II/III disease (P = 0.01), but neither VEGF-R2 nor R3 expression correlated with survival.

Conclusions

VEGF-R1, -R2 and -R3 were highly expressed in CRC cells and stromal vessels. VEGF-R1 strong positive staining correlated with shorter survival after CRC surgery.

  T Doi , N Boku , K Kato , Y Komatsu , K Yamaguchi , K Muro , Y Hamamoto , A Sato , W Koizumi , N Mizunuma and H. Takiuchi
  Objective

The addition of bevacizumab to fluoropyrimidine-based combination chemotherapy as first-line therapy for metastatic colorectal cancer results in clinically significant improvements in patient outcome. However, clinical trials have been conducted primarily in Caucasian patients with only a small proportion of Asian patients. This Phase I/II study was designed to evaluate the efficacy and safety of XELOX (capecitabine plus oxaliplatin) plus bevacizumab in Japanese patients with metastatic colorectal cancer.

Methods

Patients with previously untreated, measurable metastatic colorectal cancer received bevacizumab 7.5 mg/kg and oxaliplatin 130 mg/m2 on day 1, plus capecitabine 1000 mg/m2 twice daily on days 1–14, every 3 weeks. A three-step design evaluated in: step 1, initial safety of XELOX in six patients; step 2, initial safety of XELOX plus bevacizumab in six patients; and step 3, efficacy and safety in a further 48 patients. The primary study endpoints were safety and response rate.

Results

No dose-limiting toxicity occurred during Steps 1 and 2. Fifty-eight patients were enrolled in Steps 2 and 3 and received XELOX plus bevacizumab. In the 57 patients assessed for response, the overall response rate was 72% (95% confidence interval, 58.5–83.0). Median progression-free survival was 11.0 months (95% confidence interval, 9.6–12.5) and median overall survival was 27.4 months (95% confidence interval, 22.0–not calculated). Eight patients (14%) underwent surgery with curative intent. The most common grade 3/4 adverse events were neurosensory toxicity (17%) and neutropenia (16%).

Conclusions

XELOX plus bevacizumab is effective and has a manageable tolerability profile when given to Japanese patients with metastatic colorectal cancer.

  K Kato , M Yamaguchi Yamada and Y. Yamamoto
 

Neurochemical and morphological changes in the carotid body are induced by chronic hypoxia, leading to regulation of ventilation. In this study, we examined the time courses of changes in immunohistochemical intensity for tyrosine hydroxylase (TH) and cellular volume of glomus cells in rats exposed to hypoxia (10% O2) for up to 24 hr. Grayscale intensity for TH immunofluorescence was significantly increased in rats exposed to hypoxia for 12, 18, and 24 hr compared with control rats (p<0.05). The transectional area of glomus cells was not significantly different between experimental groups. The TH fluorescence intensity of the glomus cells exhibited a strong negative correlation with the transectional area in control rats (Spearman's = –0.70). This correlation coefficient decreased with exposure time, and it was lowest for the rats exposed to hypoxia for 18 hr ( = –0.18). The histogram of TH fluorescence intensity showed a single peak in control rats. The peaks were gradually shifted to the right and became less pronounced in hypoxia-exposed rats, suggesting that a hypoxia-induced increase in TH immunoreactivity occurred uniformly in glomus cells. In conclusion, this study demonstrates that short-term hypoxia induces an increase in TH protein expression in rat carotid body glomus cells. (J Histochem Cytochem 58:839–846, 2010)

  F Zhang , S Tsai , K Kato , D Yamanouchi , C Wang , S Rafii , B Liu and K. C. Kent
 

Bone marrow-derived progenitor cells have recently been shown to be involved in the development of intimal hyperplasia after vascular injury. Transforming growth factor-β (TGF-β) has profound stimulatory effects on intimal hyperplasia, but it is unknown whether these effects involve progenitor cell recruitment. In this study we found that although TGF-β had no direct effect on progenitor cell recruitment, conditioned media derived from vascular smooth muscle cells (VSMC) stimulated with TGF-β induced migration of both total bone marrow (BM) cells and BM-mesenchymal stem cells (MSC) and also induced MSC differentiation into smooth muscle like cells. Furthermore, overexpression of the signaling molecule Smad3 in VSMC via adenovirus-mediated gene transfer (AdSmad3) enhanced the TGF-β's chemotactic effect. Microarray analysis of VSMC stimulated by TGF-β/AdSmad3 revealed monocyte chemoattractant protein-1 (MCP-1) as a likely factor responsible for progenitor cell recruitment. We then demonstrated that TGF-β through Smad3 phosphorylation induced a robust expression of MCP-1 in VSMC. Recombinant MCP-1 mimicked the stimulatory effect of conditioned media on BM and MSC migration. In the rat carotid injury model, Smad3 overexpression significantly increased MCP-1 expression after vascular injury, consistent with our in vitro results. Interestingly, TGF-β/Smad3-induced MCP-1 was completely blocked by both Ro-32-0432 and rotterlin, suggesting protein kinase C- (PKC) may play a role in TGF-β/Smad3-induced MCP-1 expression. In summary, our data demonstrate that TGF-β, through Smad3 and PKC, stimulates VSMC production of MCP-1, which is a chemoattractant for bone marrow-derived cells, specifically MSC. Manipulation of this signaling system may provide a novel approach to inhibition of intimal hyperplasia.

 
 
 
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