Dataset Information

In Situ Fucosylation of the Wnt Co-receptor LRP6 Increases Its Endocytosis and Reduces Wnt/β-Catenin Signaling.

ABSTRACT: Wnt/β-catenin signaling regulates critical, context-dependent transcription in numerous physiological events. Among the well-documented mechanisms affecting Wnt/β-catenin activity, modification of N-glycans by L-fucose is the newest and the least understood. Using a combination of Chinese hamster ovary cell mutants with different fucosylation levels and cell-surface fucose editing (in situ fucosylation [ISF]), we report that α(1-3)-fucosylation of N-acetylglucosamine (GlcNAc) in the Galβ(1-4)-GlcNAc sequences of complex N-glycans modulates Wnt/β-catenin activity by regulating the endocytosis of low-density lipoprotein receptor-related protein 6 (LRP6). Pulse-chase experiments reveal that ISF elevates endocytosis of lipid-raft-localized LRP6, leading to the suppression of Wnt/β-catenin signaling. Remarkably, Wnt activity decreased by ISF is fully reversed by the exogenously added fucose. The combined data show that in situ cell-surface fucosylation can be exploited to regulate a specific signaling pathway via endocytosis promoted by a fucose-binding protein, thereby linking glycosylation of a receptor with its intracellular signaling.

SUBMITTER: Hong S

PROVIDER: S-EPMC7543979 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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In Situ Fucosylation of the Wnt Co-receptor LRP6 Increases Its Endocytosis and Reduces Wnt/β-Catenin Signaling.

Hong Senlian S Feng Lei L Yang Yi Y Jiang Hao H Hou Xiaomeng X Guo Peng P Marlow Florence L FL Stanley Pamela P Wu Peng P

Cell chemical biology 20200709 9

Wnt/β-catenin signaling regulates critical, context-dependent transcription in numerous physiological events. Among the well-documented mechanisms affecting Wnt/β-catenin activity, modification of N-glycans by L-fucose is the newest and the least understood. Using a combination of Chinese hamster ovary cell mutants with different fucosylation levels and cell-surface fucose editing (in situ fucosylation [ISF]), we report that α(1-3)-fucosylation of N-acetylglucosamine (GlcNAc) in the Galβ(1-4)-Gl ...[more]

PMID: 32649905

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Project description:Aberrant regulation of the Wnt/β-catenin signaling pathway is one of the major causes of colorectal cancer (CRC). Loss-of-function mutations in APC are commonly found in CRC, leading to inappropriate activation of canonical Wnt signaling. Conversely, gain-of-function mutations in KRAS and BRAF genes are detected in up to 60% of CRCs. Whereas KRAS/mitogen-activated protein kinase (MAPK) and canonical Wnt/β-catenin pathways are critical for intestinal tumorigenesis, mechanisms integrating these two important signaling pathways during CRC development are unknown. Results herein demonstrate that transformation of normal intestinal epithelial cells (IECs) by oncogenic forms of KRAS, BRAF or MEK1 was associated with a marked increase in β-catenin/TCF4 and c-MYC promoter transcriptional activities and mRNA levels of c-Myc, Axin2 and Lef1. Notably, expression of a dominant-negative mutant of T-Cell Factor 4 (ΔNTCF4) severely attenuated IEC transformation induced by oncogenic MEK1 and markedly reduced their tumorigenic and metastatic potential in immunocompromised mice. Interestingly, the Frizzled co-receptor LRP6 was phosphorylated in a MEK-dependent manner in transformed IECs and in human CRC cell lines. Expression of LRP6 mutant in which serine/threonine residues in each particular ProlineProlineProlineSerine/ThreonineProline motif were mutated to alanines (LRP6-5A) significantly reduced β-catenin/TCF4 transcriptional activity. Accordingly, MEK inhibition in human CRC cells significantly diminished β-catenin/TCF4 transcriptional activity and c-MYC mRNA and protein levels without affecting β-catenin expression or stability. Lastly, LRP6 phosphorylation was also increased in human colorectal tumors, including adenomas, in comparison with healthy adjacent normal tissues. Our data indicate that oncogenic activation of KRAS/BRAF/MEK signaling stimulates the canonical Wnt/β-catenin pathway, which in turn promotes intestinal tumor growth and invasion. Moreover, LRP6 phosphorylation by ERK1/2 may provide a unique point of convergence between KRAS/MAPK and Wnt/β-catenin signalings during oncogenesis.

Dataset Information

In Situ Fucosylation of the Wnt Co-receptor LRP6 Increases Its Endocytosis and Reduces Wnt/β-Catenin Signaling.

Publications

In Situ Fucosylation of the Wnt Co-receptor LRP6 Increases Its Endocytosis and Reduces Wnt/β-Catenin Signaling.

Similar Datasets

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