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

J. Biol. Chem. 276 (41): 37769-37778

© 2001 by The American Society for Biochemistry and Molecular Biology, Inc.

Fucosylation of Cripto Is Required for Its Ability to Facilitate Nodal Signaling*

Susan G. SchifferDagger §, Susan FoleyDagger §, Azita KaffashanDagger , Xiaoping HronowskiDagger , Anne E. ZichittellaDagger , Chang-Yeol Yeo, Konrad MiatkowskiDagger , Heather B. AdkinsDagger ||, Bruno DamonDagger , Malcolm Whitman, David Salomon||, Michele SanicolaDagger , and Kevin P. WilliamsDagger **

From Dagger  Biogen, Inc., Cambridge, Massachusetts 02142, the  Ph.D. Program in Biological and Biomedical Sciences and the Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, and the || Tumor Growth Factor Section, Laboratory of Tumor Immunology and Biology, NCI, National Institutes of Health, Bethesda, Maryland 20892

O-Linked fucose modification is rare and has been shown to occur almost exclusively within epidermal growth factor (EGF)-like modules. We have found that the EGF-CFC family member human Cripto-1 (CR) is modified with fucose and through a combination of peptide mapping, mass spectrometry, and sequence analysis localized the site of attachment to Thr-88. The identification of a fucose modification on human CR within its EGF-like domain and the presence of a consensus fucosylation site within all EGF-CFC family members suggest that this is a biologically important modification in CR, which functionally distinguishes it from the EGF ligands that bind the type 1 erbB growth factor receptors. A single CR point mutation, Thr-88 right-arrow Ala, results in a form of the protein that is not fucosylated and has substantially weaker activity in cell-based CR/Nodal signaling assays, indicating that fucosylation is functionally important for CR to facilitate Nodal signaling.

* This work was supported in part by grants from the NICHD, National Institutes of Health (to M. W.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ These authors contributed equally to this work.

** To whom correspondence should be addressed: Biogen, Inc., 14 Cambridge Center, Cambridge, MA 02142. Tel.: 617-679-3341; Fax: 617-679-3148; E-mail:

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.

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 »
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 »
Regulation of TGF-{beta} signalling by N-acetylgalactosaminyltransferase-like 1.
P. Herr, G. Korniychuk, Y. Yamamoto, K. Grubisic, and M. Oelgeschlager (2008)
Development 135, 1813-1822
   Abstract »    Full Text »    PDF »
Cripto promotes A-P axis specification independently of its stimulatory effect on Nodal autoinduction.
D. D'Andrea, G. L. Liguori, J. A. Le Good, E. Lonardo, O. Andersson, D. B. Constam, M. G. Persico, and G. Minchiotti (2008)
J. Cell Biol. 180, 597-605
   Abstract »    Full Text »    PDF »
Requirement of Glycosylphosphatidylinositol Anchor of Cripto-1 for trans Activity as a Nodal Co-receptor.
K. Watanabe, S. Hamada, C. Bianco, M. Mancino, T. Nagaoka, M. Gonzales, V. Bailly, L. Strizzi, and D. S. Salomon (2007)
J. Biol. Chem. 282, 35772-35786
   Abstract »    Full Text »    PDF »
The Threonine That Carries Fucose, but Not Fucose, Is Required for Cripto to Facilitate Nodal Signaling.
S. Shi, C. Ge, Y. Luo, X. Hou, R. S. Haltiwanger, and P. Stanley (2007)
J. Biol. Chem. 282, 20133-20141
   Abstract »    Full Text »    PDF »
The structural basis of TGF-{beta}, bone morphogenetic protein, and activin ligand binding..
S J. Lin, T. F Lerch, R. W Cook, T. S Jardetzky, and T. K Woodruff (2006)
Reproduction 132, 179-190
   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 »
XCR2, one of three Xenopus EGF-CFC genes, has a distinct role in the regulation of left-right patterning.
Y. Onuma, C.-Y. Yeo, and M. Whitman (2006)
Development 133, 237-250
   Abstract »    Full Text »    PDF »
Role of Human Cripto-1 in Tumor Angiogenesis.
C. Bianco, L. Strizzi, A. Ebert, C. Chang, A. Rehman, N. Normanno, L. Guedez, R. Salloum, E. Ginsburg, Y. Sun, et al. (2005)
J Natl Cancer Inst 97, 132-141
   Abstract »    Full Text »    PDF »
Nodal-dependent Cripto signaling promotes cardiomyogenesis and redirects the neural fate of embryonic stem cells.
S. Parisi, D. D'Andrea, C. T. Lago, E. D. Adamson, M. G. Persico, and G. Minchiotti (2003)
J. Cell Biol. 163, 303-314
   Abstract »    Full Text »    PDF »
neurotic, a novel maternal neurogenic gene, encodes an O-fucosyltransferase that is essential for Notch-Delta interactions.
T. Sasamura, N. Sasaki, F. Miyashita, S. Nakao, H. O. Ishikawa, M. Ito, M. Kitagawa, K. Harigaya, E. Spana, D. Bilder, et al. (2003)
Development 130, 4785-4795
   Abstract »    Full Text »    PDF »
Differential Terminal Fucosylation of N-Linked Glycans Versus Protein O-Fucosylation in Leukocyte Adhesion Deficiency Type II (CDG IIc).
L. Sturla, R. Rampal, R. S. Haltiwanger, F. Fruscione, A. Etzioni, and M. Tonetti (2003)
J. Biol. Chem. 278, 26727-26733
   Abstract »    Full Text »    PDF »
Fucose: biosynthesis and biological function in mammals.
D. J. Becker and J. B. Lowe (2003)
Glycobiology 13, 41R-53R
   Abstract »    Full Text »    PDF »
FRL-1, a member of the EGF-CFC family, is essential for neural differentiation in Xenopus early development.
S.-I. Yabe, K. Tanegashima, Y. Haramoto, S. Takahashi, T. Fujii, S. Kozuma, Y. Taketani, and M. Asashima (2003)
Development 130, 2071-2081
   Abstract »    Full Text »    PDF »
Protein O-fucosyltransferase 1 is an essential component of Notch signaling pathways.
S. Shi and P. Stanley (2003)
PNAS 100, 5234-5239
   Abstract »    Full Text »    PDF »
Cripto, a Multifunctional Partner in Signaling: Molecular Forms and Activities.
F. M. Rosa (2002)
Sci. STKE 2002, pe47
   Abstract »    Full Text »    PDF »
O-Glycosylation of EGF repeats: identification and initial characterization of a UDP-glucose: protein O-glucosyltransferase.
L. Shao, Y. Luo, D. J. Moloney, and R. S. Haltiwanger (2002)
Glycobiology 12, 763-770
   Abstract »    Full Text »    PDF »
Notch Ligands Are Substrates for Protein O-Fucosyltransferase-1 and Fringe.
V. M. Panin, L. Shao, L. Lei, D. J. Moloney, K. D. Irvine, and R. S. Haltiwanger (2002)
J. Biol. Chem. 277, 29945-29952
   Abstract »    Full Text »    PDF »
Dual Roles of Cripto as a Ligand and Coreceptor in the Nodal Signaling Pathway.
Y.-T. Yan, J.-J. Liu, Y. Luo, C. E, R. S. Haltiwanger, C. Abate-Shen, and M. M. Shen (2002)
Mol. Cell. Biol. 22, 4439-4449
   Abstract »    Full Text »    PDF »
Cripto-1 Activates Nodal- and ALK4-Dependent and -Independent Signaling Pathways in Mammary Epithelial Cells.
C. Bianco, H. B. Adkins, C. Wechselberger, M. Seno, N. Normanno, A. De Luca, Y. Sun, N. Khan, N. Kenney, A. Ebert, et al. (2002)
Mol. Cell. Biol. 22, 2586-2597
   Abstract »    Full Text »    PDF »
High-level and high-throughput recombinant protein production by transient transfection of suspension-growing human 293-EBNA1 cells.
Y. Durocher, S. Perret, and A. Kamen (2002)
Nucleic Acids Res. 30, e9
   Abstract »    Full Text »    PDF »
Meeting Report: Signaling Schemes for TGF-{beta}.
A. B. Roberts and R. Derynck (2001)
Sci. STKE 2001, pe43
   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