Protein O-Fucosyltransferase 2 Adds O-Fucose to Thrombospondin Type 1 Repeats

Luo, Yi; Koles, Kate; Vorndam, Wendy; Haltiwanger, Robert S.; Panin, Vladislav M.

doi:10.1074/jbc.m511975200

Cited by 121 publications

(132 citation statements)

References 43 publications

(56 reference statements)

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“…Indeed, Pofut1 function is never complemented by another enzyme nor by its paralogue, Pofut2 (47). Interestingly, the cax (for compact axial skeleton) mutation in mouse, which creates a Pofut1 hypomorphic allele due to an intracisternal A particle (IAP) insertion, more deeply affects Pofut1 expression without altering viability (48).…”

Section: Discussionmentioning

confidence: 99%

Protein O-Fucosyltransferase 1 Expression Impacts Myogenic C2C12 Cell Commitment via the Notch Signaling Pathway

Vartanian

Audfray

Jaam

et al. 2015

Molecular and Cellular Biology

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Section: Discussionmentioning

confidence: 99%

Protein O-Fucosyltransferase 1 Expression Impacts Myogenic C2C12 Cell Commitment via the Notch Signaling Pathway

Vartanian

Audfray

Jaam

et al. 2015

Molecular and Cellular Biology

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“…21,22 Deletion of FX not only eliminates O-fucose on Notch but also may affect other fucyosyltransferase activities (eg, Fut4 and Fut7 decorated selectin ligand interaction with selectin that can influence myeloid homeostasis, and Pofut2 that mediates fucosylation of thrombospondin type 1 repeats). 24,29 To determine specific roles for Notch O-fucosylation in hematopoiesis, we investigated whether inactivation of the Pofut1 gene that encodes the enzyme responsible for the addition of O-linked fucose to multiple EGF repeats on Notch would result in a similar phenotype. We therefore generated a Mx-Cre/Pofut1 F/F mouse (supplemental Figure 1A, available on the Blood Web site; see the Supplemental Materials link at the top of the online article.)…”

Section: Myeloid Hyperplasia and Impaired Lymphopoiesis In Mice Lackimentioning

confidence: 99%

Protein O-fucosyltransferase 1 (Pofut1) regulates lymphoid and myeloid homeostasis through modulation of Notch receptor ligand interactions

Yao

Huang

et al. 2011

Blood

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Notch signaling is essential for lymphocyte development and is also implicated in myelopoiesis. Notch receptors are modified by O-fucosylation catalyzed by protein O-fucosyltransferase 1 (Pofut1). Fringe enzymes add N-acetylglucosamine to O-fucose and modify Notch signaling by altering the sensitivity of Notch receptors to Notch ligands. To address physiologic functions in hematopoiesis of Notch modified by O-fucose glycans, we examined mice with inducible inactivation of Pofut1 using Mx-Cre. These mice exhibited a reduction in T lymphopoiesis and in the production of marginal-zone B cells, in addition to myeloid hyperplasia. Restoration of Notch1 signaling rescued T lymphopoiesis and the marrow myeloid hyperplasia. After marrow transfer, both cell-autonomous and environmental cues were found to contribute to lymphoid developmental defects and myeloid hyperplasia in Pofut1-deleted mice. Although Pofut1 deficiency slightly decreased cell surface expression of Notch1 and Notch2, it completely abrogated the binding of Notch receptors with Delta-like Notch ligands and suppressed downstream Notch target activation, indicating that O-fucose glycans are critical for efficient Notch-ligand binding that transduce Notch signals. The combined data support a key role for the O-fucose glycans generated by Pofut1 in Notch regulation of hematopoietic homeostasis through modulation of Notch-ligand interactions.

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“…Recently, it was shown that two distinct O-fucosylation pathways exist, specific either for EGF-like domains or TSP-1 repeats (23,24). In contrast to the modification on TSP-1 repeats, which can only be elongated by a glucose moiety, the fucose moiety on EGF-like domains can be elongated to a tetrasacharide with N-acetylglucosamine, galactose, and N-acetylneuraminic acid.…”

Section: Discussionmentioning

confidence: 99%

O-Glucosylation and O-Fucosylation Occur Together in Close Proximity on the First Epidermal Growth Factor Repeat of AMACO (VWA2 Protein)

Gebauer

Müller

Hanisch

et al. 2008

Journal of Biological Chemistry

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AMACO (VWA2 protein) is an extracellular matrix protein of unknown function associated with certain basement membranes in skin, lung, and kidney. AMACO is a member of the von Willebrand factor A-like (VWA) domain containing protein superfamily and in addition to three VWA domains it also contains two epidermal growth factor-like domains. One of these contains the rare, overlapping consensus sequences for both O-glucosylation and O-fucosylation. In earlier studies of other proteins the attachment of either core glucose and fucose moieties or of the respective elongated glycans starting with these monosaccharides has been described. By a detailed mass spectrometric analysis we show that both elongated O-glucosylated (Xyl1-3Xyl1-3Glc) and elongated O-fucosylated glycan chains (NeuAc2-3Gal1-4GlcNAc1-3Fuc) can be attached to AMACO in close proximity on the same epidermal growth factor-like domain. It has been reported that the lack of O-fucosylation can markedly decrease secretion of proteins. However, the secretion of AMACO is not significantly affected when the glycosylation sites are mutated. The number of extracellular matrix proteins carrying the overlapping consensus sequence is very limited and it could be that these modifications have a new, yet unknown function.AMACO (VWA2 protein) is a recently discovered member of the protein superfamily containing von Willebrand factor A-like (VWA) 3 domains of the type found in matrilins and collagens (1). AMACO consists of an N-terminal VWA-like domain, which is followed by a cysteine-rich region that has no obvious similarity to any other known domain. Toward the C terminus, an epidermal growth factor-like (EGF) domain, two additional VWA-like domains, and a second EGF-like domain follow (Fig. 1A). Electron microscopy and nonreducing SDS-PAGE show both monomers and higher aggregates, indicating a partial cross-linking of native AMACO via unpaired cysteines. AMACO is specifically expressed in skin, lung, and kidney. The protein is deposited in the extracellular matrix and appears to be associated with certain basement membranes that underlie epithelial cells. The function of AMACO still remains unclear. However, the localization may indicate that AMACO is either a structural component of some basement membranes or part of the anchoring structures formed on a scaffold of, e.g. collagen VII or fibrillin. Recently, in a microarray AMACO was identified as a candidate marker of colon neoplasia and found to be induced by an average of 78-fold in stage II, III, and IV colon cancers, as well as in colon adenomas and colon cancer cell lines. Epitope-tagged AMACO was detectable in the blood of mice bearing transfected human cancer xenografts indicating a potential role as a diagnostic serum marker of early stage colon cancer. Therefore, AMACO was alternatively named CCSP-2, colon cancer secreted protein-2 (2). In addition, polymorphisms in the AMACO gene were shown to be associated with dominant protection against type 1A diabetes, although a functional relevance for this linkage...

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Protein O-Fucosyltransferase 2 Adds O-Fucose to Thrombospondin Type 1 Repeats

Cited by 121 publications

References 43 publications

Protein O-Fucosyltransferase 1 Expression Impacts Myogenic C2C12 Cell Commitment via the Notch Signaling Pathway

Protein O-Fucosyltransferase 1 Expression Impacts Myogenic C2C12 Cell Commitment via the Notch Signaling Pathway

Protein O-fucosyltransferase 1 (Pofut1) regulates lymphoid and myeloid homeostasis through modulation of Notch receptor ligand interactions

O-Glucosylation and O-Fucosylation Occur Together in Close Proximity on the First Epidermal Growth Factor Repeat of AMACO (VWA2 Protein)

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