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Loss of α1,6-fucosyltransferase suppressed liver regeneration: implication of core fucose in the regulation of growth factor receptor-mediated cellular signaling.

Wang Y, Fukuda T, Isaji T, Lu J, Gu W, Lee HH, Ohkubo Y, Kamada Y, Taniguchi N, Miyoshi E, Gu J - Sci Rep (2015)

Bottom Line: Interestingly, we show that the Fut8 activities were significantly increased in the beginning of PH (~4d), but returned to the basal level in the late stage of PH.Lacking Fut8 led to delayed liver recovery in mice.This retardation mainly resulted from suppressed hepatocyte proliferation, as supported not only by a decreased phosphorylation level of epidermal growth factor (EGF) receptor and hepatocyte growth factor (HGF) receptor in the liver of Fut8(-/-) mice in vivo, but by the reduced response to exogenous EGF and HGF of the primary hepatocytes isolated from the Fut8(-/-) mice.

View Article: PubMed Central - PubMed

Affiliation: Division of Regulatory Glycobiology, Tohoku Pharmaceutical University, Sendai, Miyagi, 981-8558, Japan.

ABSTRACT
Core fucosylation is an important post-translational modification, which is catalyzed by α1,6-fucosyltransferase (Fut8). Increased expression of Fut8 has been shown in diverse carcinomas including hepatocarcinoma. In this study, we investigated the role of Fut8 expression in liver regeneration by using the 70% partial hepatectomy (PH) model, and found that Fut8 is also critical for the regeneration of liver. Interestingly, we show that the Fut8 activities were significantly increased in the beginning of PH (~4d), but returned to the basal level in the late stage of PH. Lacking Fut8 led to delayed liver recovery in mice. This retardation mainly resulted from suppressed hepatocyte proliferation, as supported not only by a decreased phosphorylation level of epidermal growth factor (EGF) receptor and hepatocyte growth factor (HGF) receptor in the liver of Fut8(-/-) mice in vivo, but by the reduced response to exogenous EGF and HGF of the primary hepatocytes isolated from the Fut8(-/-) mice. Furthermore, an administration of L-fucose, which can increase GDP-fucose synthesis through a salvage pathway, significantly rescued the delayed liver regeneration of Fut8(+/-) mice. Overall, our study provides the first direct evidence for the involvement of Fut8 in liver regeneration.

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The activities of Fut8 were increased after 70% partial hepatectomy (PH).The liver tissues were harvested for the determination of enzyme activities at indicated times as described in “Methods”. (a) A representative elution pattern on HPLC for Fut8 activities in Fut8+/+ mouse with (left panel) or without (right panel) PH. S: substrate; P: product. (b) The quantitative assay for enzyme activities in Fut8+/+ mice after PH. *, P < 0.05, compared to the group without PH (sham), which was set as 1, n = 3. (c) Reaction for synthesis of α1,6-fucose.
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f1: The activities of Fut8 were increased after 70% partial hepatectomy (PH).The liver tissues were harvested for the determination of enzyme activities at indicated times as described in “Methods”. (a) A representative elution pattern on HPLC for Fut8 activities in Fut8+/+ mouse with (left panel) or without (right panel) PH. S: substrate; P: product. (b) The quantitative assay for enzyme activities in Fut8+/+ mice after PH. *, P < 0.05, compared to the group without PH (sham), which was set as 1, n = 3. (c) Reaction for synthesis of α1,6-fucose.

Mentions: Fucosylation is one type of glycosylation. It describes the attachment of a fucose residue to N-glycans, O-glycans, and glycolipid catalyzed by a family of enzymes called fucosyltransferases (Futs)9. Among these, α1,6-fucosyltransferase (Fut8) is the only enzyme that catalyzes the transfer of a fucose from GDP-fucose to the innermost GlcNAc residue via α1,6-linkage to form core fucosylation in mammals as shown in Figure 1c. The enzymatic products, core fucosylated N-glycans, are widely distributed in a variety of glycoproteins and have been shown to play important roles in cell signaling. As examples, we previously showed that core fucosylation is crucial for the ligand binding affinity of TGF-β1 receptor10, EGF receptor11, and integrin α3β112. Lacking the core fucose of these receptors led to a marked reduction in their ligand-binding ability and downstream signaling. Recently, our group found that a loss of core fucose on activin receptors resulted in an enhancement of the formation of activin receptor complexes, which constitutively activated intracellular signaling13. These studies indicate that core fucosylation is able to negatively or positively affect signaling pathways through regulation of receptor binding ability.


Loss of α1,6-fucosyltransferase suppressed liver regeneration: implication of core fucose in the regulation of growth factor receptor-mediated cellular signaling.

Wang Y, Fukuda T, Isaji T, Lu J, Gu W, Lee HH, Ohkubo Y, Kamada Y, Taniguchi N, Miyoshi E, Gu J - Sci Rep (2015)

The activities of Fut8 were increased after 70% partial hepatectomy (PH).The liver tissues were harvested for the determination of enzyme activities at indicated times as described in “Methods”. (a) A representative elution pattern on HPLC for Fut8 activities in Fut8+/+ mouse with (left panel) or without (right panel) PH. S: substrate; P: product. (b) The quantitative assay for enzyme activities in Fut8+/+ mice after PH. *, P < 0.05, compared to the group without PH (sham), which was set as 1, n = 3. (c) Reaction for synthesis of α1,6-fucose.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4317695&req=5

f1: The activities of Fut8 were increased after 70% partial hepatectomy (PH).The liver tissues were harvested for the determination of enzyme activities at indicated times as described in “Methods”. (a) A representative elution pattern on HPLC for Fut8 activities in Fut8+/+ mouse with (left panel) or without (right panel) PH. S: substrate; P: product. (b) The quantitative assay for enzyme activities in Fut8+/+ mice after PH. *, P < 0.05, compared to the group without PH (sham), which was set as 1, n = 3. (c) Reaction for synthesis of α1,6-fucose.
Mentions: Fucosylation is one type of glycosylation. It describes the attachment of a fucose residue to N-glycans, O-glycans, and glycolipid catalyzed by a family of enzymes called fucosyltransferases (Futs)9. Among these, α1,6-fucosyltransferase (Fut8) is the only enzyme that catalyzes the transfer of a fucose from GDP-fucose to the innermost GlcNAc residue via α1,6-linkage to form core fucosylation in mammals as shown in Figure 1c. The enzymatic products, core fucosylated N-glycans, are widely distributed in a variety of glycoproteins and have been shown to play important roles in cell signaling. As examples, we previously showed that core fucosylation is crucial for the ligand binding affinity of TGF-β1 receptor10, EGF receptor11, and integrin α3β112. Lacking the core fucose of these receptors led to a marked reduction in their ligand-binding ability and downstream signaling. Recently, our group found that a loss of core fucose on activin receptors resulted in an enhancement of the formation of activin receptor complexes, which constitutively activated intracellular signaling13. These studies indicate that core fucosylation is able to negatively or positively affect signaling pathways through regulation of receptor binding ability.

Bottom Line: Interestingly, we show that the Fut8 activities were significantly increased in the beginning of PH (~4d), but returned to the basal level in the late stage of PH.Lacking Fut8 led to delayed liver recovery in mice.This retardation mainly resulted from suppressed hepatocyte proliferation, as supported not only by a decreased phosphorylation level of epidermal growth factor (EGF) receptor and hepatocyte growth factor (HGF) receptor in the liver of Fut8(-/-) mice in vivo, but by the reduced response to exogenous EGF and HGF of the primary hepatocytes isolated from the Fut8(-/-) mice.

View Article: PubMed Central - PubMed

Affiliation: Division of Regulatory Glycobiology, Tohoku Pharmaceutical University, Sendai, Miyagi, 981-8558, Japan.

ABSTRACT
Core fucosylation is an important post-translational modification, which is catalyzed by α1,6-fucosyltransferase (Fut8). Increased expression of Fut8 has been shown in diverse carcinomas including hepatocarcinoma. In this study, we investigated the role of Fut8 expression in liver regeneration by using the 70% partial hepatectomy (PH) model, and found that Fut8 is also critical for the regeneration of liver. Interestingly, we show that the Fut8 activities were significantly increased in the beginning of PH (~4d), but returned to the basal level in the late stage of PH. Lacking Fut8 led to delayed liver recovery in mice. This retardation mainly resulted from suppressed hepatocyte proliferation, as supported not only by a decreased phosphorylation level of epidermal growth factor (EGF) receptor and hepatocyte growth factor (HGF) receptor in the liver of Fut8(-/-) mice in vivo, but by the reduced response to exogenous EGF and HGF of the primary hepatocytes isolated from the Fut8(-/-) mice. Furthermore, an administration of L-fucose, which can increase GDP-fucose synthesis through a salvage pathway, significantly rescued the delayed liver regeneration of Fut8(+/-) mice. Overall, our study provides the first direct evidence for the involvement of Fut8 in liver regeneration.

Show MeSH
Related in: MedlinePlus