Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

Science 307 (5715): 1599-1603

Copyright © 2005 by the American Association for the Advancement of Science

Chaperone Activity of Protein O-Fucosyltransferase 1 Promotes Notch Receptor Folding

Tetsuya Okajima, Aiguo Xu, Liang Lei, Kenneth D. Irvine*

Abstract: Notch proteins are receptors for a conserved signaling pathway that affects numerous cell fate decisions. We found that in Drosophila, Protein O-fucosyltransferase 1 (OFUT1), an enzyme that glycosylates epidermal growth factor–like domains of Notch, also has a distinct Notch chaperone activity. OFUT1 is an endoplasmic reticulum protein, and its localization was essential for function in vivo. OFUT1 could bind to Notch, was required for the trafficking of wild-type Notch out of the endoplasmic reticulum, and could partially rescue defects in secretion and ligand binding associated with Notch point mutations. This ability of OFUT1 to facilitate folding of Notch did not require its fucosyltransferase activity. Thus, a glycosyltransferase can bind its substrate in the endoplasmic reticulum to facilitate normal folding.

Howard Hughes Medical Institute, Waksman Institute and Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, NJ 08854, USA.

* To whom correspondence should be addressed. E-mail: irvine{at}

A heterozygous mutation of GALNTL5 affects male infertility with impairment of sperm motility.
N. Takasaki, K. Tachibana, S. Ogasawara, H. Matsuzaki, J. Hagiuda, H. Ishikawa, K. Mochida, K. Inoue, N. Ogonuki, A. Ogura, et al. (2014)
PNAS 111, 1120-1125
   Abstract »    Full Text »    PDF »
Mutations in the Drosophila ortholog of the vertebrate Golgi pH regulator (GPHR) protein disturb endoplasmic reticulum and Golgi organization and affect systemic growth.
B. Charroux and J. Royet (2014)
Biology Open 3, 72-80
   Abstract »    Full Text »    PDF »
Notch signaling at a glance.
K. Hori, A. Sen, and S. Artavanis-Tsakonas (2013)
J. Cell Sci. 126, 2135-2140
   Abstract »    Full Text »    PDF »
A Mosaic Genetic Screen for Genes Involved in the Early Steps of Drosophila Oogenesis.
M. Jagut, L. Mihaila-Bodart, A. Molla-Herman, M.-F. Alin, J.-A. Lepesant, and J.-R. Huynh (2013)
g3 3, 409-425
   Abstract »    Full Text »    PDF »
TspanC8 tetraspanins regulate ADAM10/Kuzbanian trafficking and promote Notch activation in flies and mammals.
E. Dornier, F. Coumailleau, J.-F. Ottavi, J. Moretti, C. Boucheix, P. Mauduit, F. Schweisguth, and E. Rubinstein (2012)
J. Cell Biol. 199, 481-496
   Abstract »    Full Text »    PDF »
H. Takeuchi, J. Kantharia, M. K. Sethi, H. Bakker, and R. S. Haltiwanger (2012)
J. Biol. Chem. 287, 33934-33944
   Abstract »    Full Text »    PDF »
Structure of human POFUT2: insights into thrombospondin type 1 repeat fold and O-fucosylation.
C.-I. Chen, J. J. Keusch, D. Klein, D. Hess, J. Hofsteenge, and H. Gut (2012)
EMBO J. 31, 3183-3197
   Abstract »    Full Text »    PDF »
Deficient Notch signaling associated with neurogenic pecanex is compensated for by the unfolded protein response in Drosophila.
T. Yamakawa, K. Yamada, T. Sasamura, N. Nakazawa, M. Kanai, E. Suzuki, M. E. Fortini, and K. Matsuno (2012)
Development 139, 558-567
   Abstract »    Full Text »    PDF »
Notch Signaling in Sertoli Cells Regulates Cyclical Gene Expression of Hes1 but Is Dispensable for Mouse Spermatogenesis.
K. Hasegawa, Y. Okamura, and Y. Saga (2012)
Mol. Cell. Biol. 32, 206-215
   Abstract »    Full Text »    PDF »
Identification and Characterization of Genes Required for Compensatory Growth in Drosophila.
A. R. Gerhold, D. J. Richter, A. S. Yu, and I. K. Hariharan (2011)
Genetics 189, 1309-1326
   Abstract »    Full Text »    PDF »
Distinct levels of Notch activity for commitment and terminal differentiation of stem cells in the adult fly intestine.
C. N. Perdigoto, F. Schweisguth, and A. J. Bardin (2011)
Development 138, 4585-4595
   Abstract »    Full Text »    PDF »
O-Glucose Trisaccharide Is Present at High but Variable Stoichiometry at Multiple Sites on Mouse Notch1.
N. A. Rana, A. Nita-Lazar, H. Takeuchi, S. Kakuda, K. B. Luther, and R. S. Haltiwanger (2011)
J. Biol. Chem. 286, 31623-31637
   Abstract »    Full Text »    PDF »
Regulation of developmental intercellular signalling by intracellular trafficking.
B.-Z. Shilo and E. D. Schejter (2011)
EMBO J. 30, 3516-3526
   Abstract »    Full Text »    PDF »
Protein O-fucosyltransferase 1 (Pofut1) regulates lymphoid and myeloid homeostasis through modulation of Notch receptor ligand interactions.
D. Yao, Y. Huang, X. Huang, W. Wang, Q. Yan, L. Wei, W. Xin, S. Gerson, P. Stanley, J. B. Lowe, et al. (2011)
Blood 117, 5652-5662
   Abstract »    Full Text »    PDF »
Slc35c2 Promotes Notch1 Fucosylation and Is Required for Optimal Notch Signaling in Mammalian Cells.
L. Lu, X. Hou, S. Shi, C. Korner, and P. Stanley (2010)
J. Biol. Chem. 285, 36245-36254
   Abstract »    Full Text »    PDF »
Neural-specific {alpha}3-fucosylation of N-linked glycans in the Drosophila embryo requires Fucosyltransferase A and influences developmental signaling associated with O-glycosylation.
D. Rendic, M. Sharrow, T. Katoh, B. Overcarsh, K. Nguyen, J. Kapurch, K. Aoki, I. B. H. Wilson, and M. Tiemeyer (2010)
Glycobiology 20, 1353-1365
   Abstract »    Full Text »    PDF »
Role of glycans and glycosyltransferases in the regulation of Notch signaling.
H. Jafar-Nejad, J. Leonardi, and R. Fernandez-Valdivia (2010)
Glycobiology 20, 931-949
   Abstract »    Full Text »    PDF »
An O-Glycosyltransferase Promotes Cell Adhesion during Development by Influencing Secretion of an Extracellular Matrix Integrin Ligand.
L. Zhang, D. T. Tran, and K. G. Ten Hagen (2010)
J. Biol. Chem. 285, 19491-19501
   Abstract »    Full Text »    PDF »
Crumbs is required to achieve proper organ size control during Drosophila head development.
E. C. N. Richardson and F. Pichaud (2010)
Development 137, 641-650
   Abstract »    Full Text »    PDF »
Two Pathways for Importing GDP-fucose into the Endoplasmic Reticulum Lumen Function Redundantly in the O-Fucosylation of Notch in Drosophila.
H. O. Ishikawa, T. Ayukawa, M. Nakayama, S. Higashi, S. Kamiyama, S. Nishihara, K. Aoki, N. Ishida, Y. Sanai, and K. Matsuno (2010)
J. Biol. Chem. 285, 4122-4129
   Abstract »    Full Text »    PDF »
Identification of Glycosyltransferase 8 Family Members as Xylosyltransferases Acting on O-Glucosylated Notch Epidermal Growth Factor Repeats.
M. K. Sethi, F. F. R. Buettner, V. B. Krylov, H. Takeuchi, N. E. Nifantiev, R. S. Haltiwanger, R. Gerardy-Schahn, and H. Bakker (2010)
J. Biol. Chem. 285, 1582-1586
   Abstract »    Full Text »    PDF »
The Cytoplasmic Tail of GM3 Synthase Defines Its Subcellular Localization, Stability, and In Vivo Activity.
S. Uemura, S. Yoshida, F. Shishido, and J.-i. Inokuchi (2009)
Mol. Biol. Cell 20, 3088-3100
   Abstract »    Full Text »    PDF »
Association of {beta}-1,3-N-acetylglucosaminyltransferase 1 and {beta}-1,4-galactosyltransferase 1, trans-Golgi enzymes involved in coupled poly-N-acetyllactosamine synthesis.
P. L Lee, J. J Kohler, and S. R Pfeffer (2009)
Glycobiology 19, 655-664
   Abstract »    Full Text »    PDF »
A Notch updated.
A.-C. Tien, A. Rajan, and H. J. Bellen (2009)
J. Cell Biol. 184, 621-629
   Abstract »    Full Text »    PDF »
Activity, Splice Variants, Conserved Peptide Motifs, and Phylogeny of Two New {alpha}1,3-Fucosyltransferase Families (FUT10 and FUT11).
R. Mollicone, S. E. H. Moore, N. Bovin, M. Garcia-Rosasco, J.-J. Candelier, I. Martinez-Duncker, and R. Oriol (2009)
J. Biol. Chem. 284, 4723-4738
   Abstract »    Full Text »    PDF »
Glycobiology on the fly: Developmental and mechanistic insights from Drosophila.
K. G. T. Hagen, L. Zhang, E Tian, and Y. Zhang (2009)
Glycobiology 19, 102-111
   Abstract »    Full Text »    PDF »
Structural and Mechanistic Insights into Lunatic Fringe from a Kinetic Analysis of Enzyme Mutants.
K. B. Luther, H. Schindelin, and R. S. Haltiwanger (2009)
J. Biol. Chem. 284, 3294-3305
   Abstract »    Full Text »    PDF »
Notch signaling is required for the maintenance of enteric neural crest progenitors.
Y. Okamura and Y. Saga (2008)
Development 135, 3555-3565
   Abstract »    Full Text »    PDF »
Ero1L, a thiol oxidase, is required for Notch signaling through cysteine bridge formation of the Lin12-Notch repeats in Drosophila melanogaster.
A.-C. Tien, A. Rajan, K. L. Schulze, H. D. Ryoo, M. Acar, H. Steller, and H. J. Bellen (2008)
J. Cell Biol. 182, 1113-1125
   Abstract »    Full Text »    PDF »
Biological Functions of Glycosyltransferase Genes Involved in O-fucose Glycan Synthesis.
T. Okajima, A. Matsuura, and T. Matsuda (2008)
J. Biochem. 144, 1-6
   Abstract »    Full Text »    PDF »
Roles of Pofut1 and O-Fucose in Mammalian Notch Signaling.
M. Stahl, K. Uemura, C. Ge, S. Shi, Y. Tashima, and P. Stanley (2008)
J. Biol. Chem. 283, 13638-13651
   Abstract »    Full Text »    PDF »
Cross-regulation of Ngn1 and Math1 coordinates the production of neurons and sensory hair cells during inner ear development.
S. Raft, E. J. Koundakjian, H. Quinones, C. S. Jayasena, L. V. Goodrich, J. E. Johnson, N. Segil, and A. K. Groves (2007)
Development 134, 4405-4415
   Abstract »    Full Text »    PDF »
A protein associated with Toll-like receptor (TLR) 4 (PRAT4A) is required for TLR-dependent immune responses.
K. Takahashi, T. Shibata, S. Akashi-Takamura, T. Kiyokawa, Y. Wakabayashi, N. Tanimura, T. Kobayashi, F. Matsumoto, R. Fukui, T. Kouro, et al. (2007)
J. Exp. Med. 204, 2963-2976
   Abstract »    Full Text »    PDF »
Cell and molecular biology of Notch.
U.-M. Fiuza and A. M. Arias (2007)
J. Endocrinol. 194, 459-474
   Abstract »    Full Text »    PDF »
The expression and functions of glycoconjugates in neural stem cells.
M. Yanagisawa and R. K Yu (2007)
Glycobiology 17, 57R-74R
   Abstract »    Full Text »    PDF »
O-Fucosylation Is Required for ADAMTS13 Secretion.
L. M. Ricketts, M. Dlugosz, K. B. Luther, R. S. Haltiwanger, and E. M. Majerus (2007)
J. Biol. Chem. 282, 17014-17023
   Abstract »    Full Text »    PDF »
O-Fucosylation of Thrombospondin Type 1 Repeats in ADAMTS-like-1/Punctin-1 Regulates Secretion: IMPLICATIONS FOR THE ADAMTS SUPERFAMILY.
L. W. Wang, M. Dlugosz, R. P. T. Somerville, M. Raed, R. S. Haltiwanger, and S. S. Apte (2007)
J. Biol. Chem. 282, 17024-17031
   Abstract »    Full Text »    PDF »
Crystal structure of mammalian {alpha}1,6-fucosyltransferase, FUT8.
H. Ihara, Y. Ikeda, S. Toma, X. Wang, T. Suzuki, J. Gu, E. Miyoshi, T. Tsukihara, K. Honke, A. Matsumoto, et al. (2007)
Glycobiology 17, 455-466
   Abstract »    Full Text »    PDF »
The O-fucosyltransferase O-fut1 is an extracellular component that is essential for the constitutive endocytic trafficking of Notch in Drosophila.
T. Sasamura, H. O. Ishikawa, N. Sasaki, S. Higashi, M. Kanai, S. Nakao, T. Ayukawa, T. Aigaki, K. Noda, E. Miyoshi, et al. (2007)
Development 134, 1347-1356
   Abstract »    Full Text »    PDF »
Functional Roles for {beta}1,4-N-Acetlygalactosaminyltransferase-A in Drosophila Larval Neurons and Muscles.
N. Haines and B. A. Stewart (2007)
Genetics 175, 671-679
   Abstract »    Full Text »    PDF »
Identification and Characterization of abeta1,3-Glucosyltransferase That Synthesizes the Glc-beta1,3-Fuc Disaccharide on Thrombospondin Type 1 Repeats.
K. Kozma, J. J. Keusch, B. Hegemann, K. B. Luther, D. Klein, D. Hess, R. S. Haltiwanger, and J. Hofsteenge (2006)
J. Biol. Chem. 281, 36742-36751
   Abstract »    Full Text »    PDF »
Molecular cloning and characterization of a novel human {beta}1,3-glucosyltransferase, which is localized at the endoplasmic reticulum and glucosylates O-linked fucosylglycan on thrombospondin type 1 repeat domain.
T. Sato, M. Sato, K. Kiyohara, M. Sogabe, T. Shikanai, N. Kikuchi, A. Togayachi, H. Ishida, H. Ito, A. Kameyama, et al. (2006)
Glycobiology 16, 1194-1206
   Abstract »    Full Text »    PDF »
Fucosylation in prokaryotes and eukaryotes.
B. Ma, J. L. Simala-Grant, and D. E. Taylor (2006)
Glycobiology 16, 158R-184R
   Abstract »    Full Text »    PDF »
Molecular evolution of protein O-fucosyltransferase genes and splice variants.
C. Loriol, F. Dupuy, R. Rampal, M.A. Dlugosz, R.S. Haltiwanger, A. Maftah, and A. Germot (2006)
Glycobiology 16, 736-747
   Abstract »    Full Text »    PDF »
Two Distinct Pathways for O-Fucosylation of Epidermal Growth Factor-like or Thrombospondin Type 1 Repeats.
Y. Luo, A. Nita-Lazar, and R. S. Haltiwanger (2006)
J. Biol. Chem. 281, 9385-9392
   Abstract »    Full Text »    PDF »
Protein O-Fucosyltransferase 2 Adds O-Fucose to Thrombospondin Type 1 Repeats.
Y. Luo, K. Koles, W. Vorndam, R. S. Haltiwanger, and V. M. Panin (2006)
J. Biol. Chem. 281, 9393-9399
   Abstract »    Full Text »    PDF »
Reaction mechanism and substrate specificity for nucleotide sugar of mammalian {alpha}1,6-fucosyltransferase--a large-scale preparation and characterization of recombinant human FUT8.
H. Ihara, Y. Ikeda, and N. Taniguchi (2006)
Glycobiology 16, 333-342
   Abstract »    Full Text »    PDF »
Presenilin-Based Genetic Screens in Drosophila melanogaster Identify Novel Notch Pathway Modifiers.
M. B. Mahoney, A. L. Parks, D. A. Ruddy, S. Y. K. Tiong, H. Esengil, A. C. Phan, P. Philandrinos, C. G. Winter, R. Chatterjee, K. Huppert, et al. (2006)
Genetics 172, 2309-2324
   Abstract »    Full Text »    PDF »
The twisted Gene Encodes Drosophila Protein O-Mannosyltransferase 2 and Genetically Interacts With the rotated abdomen Gene Encoding Drosophila Protein O-Mannosyltransferase 1.
D. Lyalin, K. Koles, S. D. Roosendaal, E. Repnikova, L. Van Wechel, and V. M. Panin (2006)
Genetics 172, 343-353
   Abstract »    Full Text »    PDF »
Notch deficiency implicated in the pathogenesis of congenital disorder of glycosylation IIc.
H. O. Ishikawa, S. Higashi, T. Ayukawa, T. Sasamura, M. Kitagawa, K. Harigaya, K. Aoki, N. Ishida, Y. Sanai, and K. Matsuno (2005)
PNAS 102, 18532-18537
   Abstract »    Full Text »    PDF »
Canonical Notch Signaling Is Dispensable for Early Cell Fate Specifications in Mammals.
S. Shi, M. Stahl, L. Lu, and P. Stanley (2005)
Mol. Cell. Biol. 25, 9503-9508
   Abstract »    Full Text »    PDF »
Core fucosylation of N-linked glycans in leukocyte adhesion deficiency/congenital disorder of glycosylation IIc fibroblasts.
L. Sturla, F. Fruscione, K. Noda, E. Miyoshi, N. Taniguchi, P. Contini, and M. Tonetti (2005)
Glycobiology 15, 924-934
   Abstract »    Full Text »    PDF »
Highly Conserved O-Fucose Sites Have Distinct Effects on Notch1 Function.
R. Rampal, J. F. Arboleda-Velasquez, A. Nita-Lazar, K. S. Kosik, and R. S. Haltiwanger (2005)
J. Biol. Chem. 280, 32133-32140
   Abstract »    Full Text »    PDF »
Regions of Drosophila Notch That Contribute to Ligand Binding and the Modulatory Influence of Fringe.
A. Xu, L. Lei, and K. D. Irvine (2005)
J. Biol. Chem. 280, 30158-30165
   Abstract »    Full Text »    PDF »
CADASIL mutations impair Notch3 glycosylation by Fringe.
J. F. Arboleda-Velasquez, R. Rampal, E. Fung, D. C. Darland, M. Liu, M. C. Martinez, C. P. Donahue, M. F. Navarro-Gonzalez, P. Libby, P. A. D'Amore, et al. (2005)
Hum. Mol. Genet. 14, 1631-1639
   Abstract »    Full Text »    PDF »
CELL BIOLOGY: Does Notch Take the Sweet Road to Success?.
J. B. Lowe (2005)
Science 307, 1570-1572
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882