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.
Subscribe

Logo for

Science 293 (5535): 1663-1666

Copyright © 2001 by the American Association for the Advancement of Science

Regulation of Wnt Signaling and Embryo Patterning by an Extracellular Sulfatase

Gurtej K. Dhoot,1 Marcus K. Gustafsson,2 Xingbin Ai,2 Weitao Sun,2 David M. Standiford,2 Charles P. Emerson Jr.2*

The developmental signaling functions of cell surface heparan sulfate proteoglycans (HSPGs) are dependent on their sulfation states. Here, we report the identification of QSulf1, the avian ortholog of an evolutionarily conserved protein family related to heparan-specific N-acetyl glucosamine sulfatases. QSulf1 expression is induced by Sonic hedgehog in myogenic somite progenitors in quail embryos and is required for the activation of MyoD, a Wnt-induced regulator of muscle specification. QSulf1 is localized on the cell surface and regulates heparan-dependent Wnt signaling in C2C12 myogenic progenitor cells through a mechanism that requires its catalytic activity, providing evidence that QSulf1 regulates Wnt signaling through desulfation of cell surface HSPGs.

1 Department of Basic Veterinary Sciences, The Royal Veterinary College, University of London, Royal College Street, London NW1 OTU, UK.
2 Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, 1157 BRBII/III, 421 Curie Boulevard, Philadelphia, PA 19104-6058, USA
*   To whom correspondence should be addressed. E-mail: emersonc{at}mail.med.upenn.edu

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Overexpression of Sulf2 in idiopathic pulmonary fibrosis.
X. Yue, J. Lu, L. Auduong, M. D. Sides, and J. A. Lasky (2013)
Glycobiology 23, 709-719
   Abstract »    Full Text »    PDF »
The transition from differentiation to growth during dermomyotome-derived myogenesis depends on temporally restricted hedgehog signaling.
N. Kahane, V. Ribes, A. Kicheva, J. Briscoe, and C. Kalcheim (2013)
Development 140, 1740-1750
   Abstract »    Full Text »    PDF »
Glycosaminoglycan Glycomics Using Mass Spectrometry.
J. Zaia (2013)
Mol. Cell. Proteomics 12, 885-892
   Abstract »    Full Text »    PDF »
The Role of Drosophila Heparan Sulfate 6-O-Endosulfatase in Sulfation Compensation.
K. Dejima, A. Kleinschmit, M. Takemura, P. Y. Choi, A. Kinoshita-Toyoda, H. Toyoda, and H. Nakato (2013)
J. Biol. Chem. 288, 6574-6582
   Abstract »    Full Text »    PDF »
Drosophila Heparan Sulfate 6-O-Endosulfatase Sulf1 Facilitates Wingless (Wg) Protein Degradation.
A. Kleinschmit, M. Takemura, K. Dejima, P. Y. Choi, and H. Nakato (2013)
J. Biol. Chem. 288, 5081-5089
   Abstract »    Full Text »    PDF »
Sulfatase 1 Promotes the Motor Neuron-to-Oligodendrocyte Fate Switch by Activating Shh Signaling in Olig2 Progenitors of the Embryonic Ventral Spinal Cord.
Y. Touahri, N. Escalas, B. Benazeraf, P. Cochard, C. Danesin, and C. Soula (2012)
J. Neurosci. 32, 18018-18034
   Abstract »    Full Text »    PDF »
Differential Sulfation Remodelling of Heparan Sulfate by Extracellular 6-O-Sulfatases Regulates Fibroblast Growth Factor-Induced Boundary Formation by Glial Cells: Implications for Glial Cell Transplantation.
J. R. Higginson, S. M. Thompson, A. Santos-Silva, S. E. Guimond, J. E. Turnbull, and S. C. Barnett (2012)
J. Neurosci. 32, 15902-15912
   Abstract »    Full Text »    PDF »
Substrate specificity of 6-O-endosulfatase (Sulf-2) and its implications in synthesizing anticoagulant heparan sulfate.
E. H. Pempe, T. C. Burch, C. J. Law, and J. Liu (2012)
Glycobiology 22, 1353-1362
   Abstract »    Full Text »    PDF »
Heparan Sulfate 6-O-endosulfatases (Sulfs) Coordinate the Wnt Signaling Pathways to Regulate Myoblast Fusion during Skeletal Muscle Regeneration.
T. H. Tran, X. Shi, J. Zaia, and X. Ai (2012)
J. Biol. Chem. 287, 32651-32664
   Abstract »    Full Text »    PDF »
New Negative Feedback Regulators of Egfr Signaling in Drosophila.
J. P. Butchar, D. Cain, S. N. Manivannan, A. D. McCue, L. Bonanno, S. Halula, S. Truesdell, C. L. Austin, T. L. Jacobsen, and A. Simcox (2012)
Genetics 191, 1213-1226
   Abstract »    Full Text »    PDF »
Roles of Heparan Sulfate Sulfation in Dentinogenesis.
S. Hayano, H. Kurosaka, T. Yanagita, I. Kalus, F. Milz, Y. Ishihara, M. N. Islam, N. Kawanabe, M. Saito, H. Kamioka, et al. (2012)
J. Biol. Chem. 287, 12217-12229
   Abstract »    Full Text »    PDF »
Organ-specific Sulfation Patterns of Heparan Sulfate Generated by Extracellular Sulfatases Sulf1 and Sulf2 in Mice.
S. Nagamine, M. Tamba, H. Ishimine, K. Araki, K. Shiomi, T. Okada, T. Ohto, S. Kunita, S. Takahashi, R. G. P. Wismans, et al. (2012)
J. Biol. Chem. 287, 9579-9590
   Abstract »    Full Text »    PDF »
Mucopolysaccharidosis Type I, Unique Structure of Accumulated Heparan Sulfate and Increased N-Sulfotransferase Activity in Mice Lacking {alpha}-L-iduronidase.
R. J. Holley, A. Deligny, W. Wei, H. A. Watson, M. R. Ninonuevo, A. Dagalv, J. A. Leary, B. W. Bigger, L. Kjellen, and C. L. R. Merry (2011)
J. Biol. Chem. 286, 37515-37524
   Abstract »    Full Text »    PDF »
WT1-Dependent Sulfatase Expression Maintains the Normal Glomerular Filtration Barrier.
V. A. Schumacher, U. Schlotzer-Schrehardt, S. A. Karumanchi, X. Shi, J. Zaia, S. Jeruschke, D. Zhang, H. Pavenstadt, A. Drenckhan, K. Amann, et al. (2011)
J. Am. Soc. Nephrol. 22, 1286-1296
   Abstract »    Full Text »    PDF »
Genetic Analysis of the Heparan Modification Network in Caenorhabditis elegans.
R. A. Townley and H. E. Bulow (2011)
J. Biol. Chem. 286, 16824-16831
   Abstract »    Full Text »    PDF »
HSulf-1 Modulates FGF2- and Hypoxia-Mediated Migration and Invasion of Breast Cancer Cells.
A. Khurana, P. Liu, P. Mellone, L. Lorenzon, B. Vincenzi, K. Datta, B. Yang, R. J. Linhardt, W. Lingle, J. Chien, et al. (2011)
Cancer Res. 71, 2152-2161
   Abstract »    Full Text »    PDF »
MicroRNA-218 Regulates Vascular Patterning by Modulation of Slit-Robo Signaling.
E. M. Small, L. B. Sutherland, K. N. Rajagopalan, S. Wang, and E. N. Olson (2010)
Circ. Res. 107, 1336-1344
   Abstract »    Full Text »    PDF »
Sulfatase modifying factor 1-mediated fibroblast growth factor signaling primes hematopoietic multilineage development.
M. Buono, I. Visigalli, R. Bergamasco, A. Biffi, and M. P. Cosma (2010)
J. Exp. Med. 207, 1647-1660
   Abstract »    Full Text »    PDF »
Sulfatase 1 Is an Inhibitor of Ductal Morphogenesis with Sexually Dimorphic Expression in the Urogenital Sinus.
R. A. Buresh, S. L. Kuslak, M. A. Rusch, C. M. Vezina, S. B. Selleck, and P. C. Marker (2010)
Endocrinology 151, 3420-3431
   Abstract »    Full Text »    PDF »
Drosophila Tey represses transcription of the repulsive cue Toll and generates neuromuscular target specificity.
M. Inaki, M. Shinza-Kameda, A. Ismat, M. Frasch, and A. Nose (2010)
Development 137, 2139-2146
   Abstract »    Full Text »    PDF »
Conditional Ablation of the Heparan Sulfate-synthesizing Enzyme Ext1 Leads to Dysregulation of Bone Morphogenic Protein Signaling and Severe Skeletal Defects.
Y. Matsumoto, K. Matsumoto, F. Irie, J.-i. Fukushi, W. B. Stallcup, and Y. Yamaguchi (2010)
J. Biol. Chem. 285, 19227-19234
   Abstract »    Full Text »    PDF »
Extracellular sulfatases support cartilage homeostasis by regulating BMP and FGF signaling pathways.
S. Otsuki, S. R. Hanson, S. Miyaki, S. P. Grogan, M. Kinoshita, H. Asahara, C.-H. Wong, and M. K. Lotz (2010)
PNAS 107, 10202-10207
   Abstract »    Full Text »    PDF »
Sulf1A and HGF regulate satellite-cell growth.
R. Gill, L. Hitchins, F. Fletcher, and G. K. Dhoot (2010)
J. Cell Sci. 123, 1873-1883
   Abstract »    Full Text »    PDF »
Direct detection of HSulf-1 and HSulf-2 activities on extracellular heparan sulfate and their inhibition by PI-88.
M. M. Hossain, T. Hosono-Fukao, R. Tang, N. Sugaya, T. H van Kuppevelt, G. J Jenniskens, K. Kimata, S. D Rosen, and K. Uchimura (2010)
Glycobiology 20, 175-186
   Abstract »    Full Text »    PDF »
Tracking footprints of artificial selection in the dog genome.
J. M. Akey, A. L. Ruhe, D. T. Akey, A. K. Wong, C. F. Connelly, J. Madeoy, T. J. Nicholas, and M. W. Neff (2010)
PNAS 107, 1160-1165
   Abstract »    Full Text »    PDF »
Heparin/Heparan Sulfate 6-O-Sulfatase from Flavobacterium heparinum: INTEGRATED STRUCTURAL AND BIOCHEMICAL INVESTIGATION OF ENZYME ACTIVE SITE AND SUBSTRATE SPECIFICITY.
J. R. Myette, V. Soundararajan, Z. Shriver, R. Raman, and R. Sasisekharan (2009)
J. Biol. Chem. 284, 35177-35188
   Abstract »    Full Text »    PDF »
Heparan Sulfate Proteoglycan Modulation of Wnt5A Signal Transduction in Metastatic Melanoma Cells.
M. P. O'Connell, J. L. Fiori, E. K. Kershner, B. P. Frank, F. E. Indig, D. D. Taub, K. S. Hoek, and A. T. Weeraratna (2009)
J. Biol. Chem. 284, 28704-28712
   Abstract »    Full Text »    PDF »
Characterization of the Human Sulfatase Sulf1 and Its High Affinity Heparin/Heparan Sulfate Interaction Domain.
M.-A. Frese, F. Milz, M. Dick, W. C. Lamanna, and T. Dierks (2009)
J. Biol. Chem. 284, 28033-28044
   Abstract »    Full Text »    PDF »
Functional Consequences of the Subdomain Organization of the Sulfs.
R. Tang and S. D. Rosen (2009)
J. Biol. Chem. 284, 21505-21514
   Abstract »    Full Text »    PDF »
Sulf Loss Influences N-, 2-O-, and 6-O-Sulfation of Multiple Heparan Sulfate Proteoglycans and Modulates Fibroblast Growth Factor Signaling.
W. C. Lamanna, M.-A. Frese, M. Balleininger, and T. Dierks (2008)
J. Biol. Chem. 283, 27724-27735
   Abstract »    Full Text »    PDF »
Transforming Growth Factor-{beta}1 Induces Heparan Sulfate 6-O-Endosulfatase 1 Expression in Vitro and in Vivo.
X. Yue, X. Li, H. T. Nguyen, D. R. Chin, D. E. Sullivan, and J. A. Lasky (2008)
J. Biol. Chem. 283, 20397-20407
   Abstract »    Full Text »    PDF »
Arylsulfatase G, a Novel Lysosomal Sulfatase.
M.-A. Frese, S. Schulz, and T. Dierks (2008)
J. Biol. Chem. 283, 11388-11395
   Abstract »    Full Text »    PDF »
6-O-Sulfation of Heparan Sulfate Differentially Regulates Various Fibroblast Growth Factor-dependent Signalings in Culture.
N. Sugaya, H. Habuchi, N. Nagai, S. Ashikari-Hada, and K. Kimata (2008)
J. Biol. Chem. 283, 10366-10376
   Abstract »    Full Text »    PDF »
Quail Sulf1 Function Requires Asparagine-linked Glycosylation.
R. K. Ambasta, X. Ai, and C. P. Emerson Jr. (2007)
J. Biol. Chem. 282, 34492-34499
   Abstract »    Full Text »    PDF »
SULF1 and SULF2 regulate heparan sulfate-mediated GDNF signaling for esophageal innervation.
X. Ai, T. Kitazawa, A.-T. Do, M. Kusche-Gullberg, P. A. Labosky, and C. P. Emerson Jr (2007)
Development 134, 3327-3338
   Abstract »    Full Text »    PDF »
Essential Role of Heparan Sulfate 2-O-Sulfotransferase in Chick Limb Bud Patterning and Development.
T. Kobayashi, H. Habuchi, K. Tamura, H. Ide, and K. Kimata (2007)
J. Biol. Chem. 282, 19589-19597
   Abstract »    Full Text »    PDF »
Mice Deficient in Heparan Sulfate 6-O-Sulfotransferase-1 Exhibit Defective Heparan Sulfate Biosynthesis, Abnormal Placentation, and Late Embryonic Lethality.
H. Habuchi, N. Nagai, N. Sugaya, F. Atsumi, R. L. Stevens, and K. Kimata (2007)
J. Biol. Chem. 282, 15578-15588
   Abstract »    Full Text »    PDF »
Regulation of Heparan Sulfate 6-O-Sulfation by beta-Secretase Activity.
N. Nagai, H. Habuchi, S. Kitazume, H. Toyoda, Y. Hashimoto, and K. Kimata (2007)
J. Biol. Chem. 282, 14942-14951
   Abstract »    Full Text »    PDF »
Gene Trap Disruption of the Mouse Heparan Sulfate 6-O-Endosulfatase Gene, Sulf2.
D. H. Lum, J. Tan, S. D. Rosen, and Z. Werb (2007)
Mol. Cell. Biol. 27, 678-688
   Abstract »    Full Text »    PDF »
Genomewide Expression Profiling in the Zebrafish Embryo Identifies Target Genes Regulated by Hedgehog Signaling During Vertebrate Development.
J. Xu, B. P. Srinivas, S. Y. Tay, A. Mak, X. Yu, S. G. P. Lee, H. Yang, K. R. Govindarajan, B. Leong, G. Bourque, et al. (2006)
Genetics 174, 735-752
   Abstract »    Full Text »    PDF »
Specific and flexible roles of heparan sulfate modifications in Drosophila FGF signaling.
K. Kamimura, T. Koyama, H. Habuchi, R. Ueda, M. Masu, K. Kimata, and H. Nakato (2006)
J. Cell Biol. 174, 773-778
   Abstract »    Full Text »    PDF »
Molecular Profiling of Laser-Microdissected Matched Tumor and Normal Breast Tissue Identifies Karyopherin {alpha}2 as a Potential Novel Prognostic Marker in Breast Cancer..
E. Dahl, G. Kristiansen, K. Gottlob, I. Klaman, E. Ebner, B. Hinzmann, K. Hermann, C. Pilarsky, M. Durst, M. Klinkhammer-Schalke, et al. (2006)
Clin. Cancer Res. 12, 3950-3960
   Abstract »    Full Text »    PDF »
Mouse Cristin/R-spondin Family Proteins Are Novel Ligands for the Frizzled 8 and LRP6 Receptors and Activate beta-Catenin-dependent Gene Expression.
J.-S. Nam, T. J. Turcotte, P. F. Smith, S. Choi, and J. K. Yoon (2006)
J. Biol. Chem. 281, 13247-13257
   Abstract »    Full Text »    PDF »
Ventral neural progenitors switch toward an oligodendroglial fate in response to increased Sonic hedgehog (Shh) activity: involvement of Sulfatase 1 in modulating Shh signaling in the ventral spinal cord..
C. Danesin, E. Agius, N. Escalas, X. Ai, C. Emerson, P. Cochard, and C. Soula (2006)
J. Neurosci. 26, 5037-5048
   Abstract »    Full Text »    PDF »
Inhibition or Activation of Apert Syndrome FGFR2 (S252W) Signaling by Specific Glycosaminoglycans.
L. M. McDowell, B. A. Frazier, D. R. Studelska, K. Giljum, J. Chen, J. Liu, K. Yu, D. M. Ornitz, and L. Zhang (2006)
J. Biol. Chem. 281, 6924-6930
   Abstract »    Full Text »    PDF »
Overexpression of Heparan Sulfate 6-O-Sulfotransferases in Human Embryonic Kidney 293 Cells Results in Increased N-Acetylglucosaminyl 6-O-Sulfation.
A.-T. Do, E. Smeds, D. Spillmann, and M. Kusche-Gullberg (2006)
J. Biol. Chem. 281, 5348-5356
   Abstract »    Full Text »    PDF »
Substrate Specificity and Domain Functions of Extracellular Heparan Sulfate 6-O-Endosulfatases, QSulf1 and QSulf2.
X. Ai, A.-T. Do, M. Kusche-Gullberg, U. Lindahl, K. Lu, and C. P. Emerson Jr. (2006)
J. Biol. Chem. 281, 4969-4976
   Abstract »    Full Text »    PDF »
HSulf-1 and HSulf-2 Are Potent Inhibitors of Myeloma Tumor Growth in Vivo.
Y. Dai, Y. Yang, V. MacLeod, X. Yue, A. C. Rapraeger, Z. Shriver, G. Venkataraman, R. Sasisekharan, and R. D. Sanderson (2005)
J. Biol. Chem. 280, 40066-40073
   Abstract »    Full Text »    PDF »
Specific Structural Features of Heparan Sulfate Proteoglycans Potentiate Neuregulin-1 Signaling.
M. S. Pankonin, J. T. Gallagher, and J. A. Loeb (2005)
J. Biol. Chem. 280, 383-388
   Abstract »    Full Text »    PDF »
Functions of heparan sulfate proteoglycans in cell signaling during development.
X. Lin (2004)
Development 131, 6009-6021
   Abstract »    Full Text »    PDF »
Identification of candidate cancer-causing genes in mouse brain tumors by retroviral tagging.
F. K. Johansson, J. Brodd, C. Eklof, M. Ferletta, G. Hesselager, C.-F. Tiger, L. Uhrbom, and B. Westermark (2004)
PNAS 101, 11334-11337
   Abstract »    Full Text »    PDF »
Abrogation of heparan sulfate synthesis in Drosophila disrupts the Wingless, Hedgehog and Decapentaplegic signaling pathways.
D. J. Bornemann, J. E. Duncan, W. Staatz, S. Selleck, and R. Warrior (2004)
Development 131, 1927-1938
   Abstract »    Full Text »    PDF »
QSulf1, a heparan sulfate 6-O-endosulfatase, inhibits fibroblast growth factor signaling in mesoderm induction and angiogenesis.
S. Wang, X. Ai, S. D. Freeman, M. E. Pownall, Q. Lu, D. S. Kessler, and C. P. Emerson Jr. (2004)
PNAS 101, 4833-4838
   Abstract »    Full Text »    PDF »
Domain-specific Modification of Heparan Sulfate by Qsulf1 Modulates the Binding of the Bone Morphogenetic Protein Antagonist Noggin.
B. L. Viviano, S. Paine-Saunders, N. Gasiunas, J. Gallagher, and S. Saunders (2004)
J. Biol. Chem. 279, 5604-5611
   Abstract »    Full Text »    PDF »
Immune Activation of NF-{kappa}B and JNK Requires Drosophila TAK1.
N. Silverman, R. Zhou, R. L. Erlich, M. Hunter, E. Bernstein, D. Schneider, and T. Maniatis (2003)
J. Biol. Chem. 278, 48928-48934
   Abstract »    Full Text »    PDF »
Spatial and temporal expression of heparan sulfate in mouse development regulates FGF and FGF receptor assembly.
B. L. Allen and A. C. Rapraeger (2003)
J. Cell Biol. 163, 637-648
   Abstract »    Full Text »    PDF »
Heparan Sulfate 6-O-Sulfotransferase Is Essential for Muscle Development in Zebrafish.
R. J. Bink, H. Habuchi, Z. Lele, E. Dolk, J. Joore, G.-J. Rauch, R. Geisler, S. W. Wilson, J. den Hertog, K. Kimata, et al. (2003)
J. Biol. Chem. 278, 31118-31127
   Abstract »    Full Text »    PDF »
QSulf1 remodels the 6-O sulfation states of cell surface heparan sulfate proteoglycans to promote Wnt signaling.
X. Ai, A.-T. Do, O. Lozynska, M. Kusche-Gullberg, U. Lindahl, and C. P. Emerson Jr. (2003)
J. Cell Biol. 162, 341-351
   Abstract »    Full Text »    PDF »
Molecular Cloning and Identification of 3'-Phosphoadenosine 5'-Phosphosulfate Transporter.
S. Kamiyama, T. Suda, R. Ueda, M. Suzuki, R. Okubo, N. Kikuchi, Y. Chiba, S. Goto, H. Toyoda, K. Saigo, et al. (2003)
J. Biol. Chem. 278, 25958-25963
   Abstract »    Full Text »    PDF »
Loss of HSulf-1 Up-regulates Heparin-binding Growth Factor Signaling in Cancer.
J. Lai, J. Chien, J. Staub, R. Avula, E. L. Greene, T. A. Matthews, D. I. Smith, S. H. Kaufmann, L. R. Roberts**, and V. Shridhar** (2003)
J. Biol. Chem. 278, 23107-23117
   Abstract »    Full Text »    PDF »
Wnt signaling mediates reorientation of outer hair cell stereociliary bundles in the mammalian cochlea.
A. Dabdoub, M. J. Donohue, A. Brennan, V. Wolf, M. Montcouquiol, D. A. Sassoon, J.-C. Hseih, J. S. Rubin, P. C. Salinas, and M. W. Kelley (2003)
Development 130, 2375-2384
   Abstract »    Full Text »    PDF »
Structural specificity of heparin binding in the fibroblast growth factor family of proteins.
R. Raman, G. Venkataraman, S. Ernst, V. Sasisekharan, and R. Sasisekharan (2003)
PNAS 100, 2357-2362
   Abstract »    Full Text »    PDF »
Cloning and Characterization of Two Extracellular Heparin-degrading Endosulfatases in Mice and Humans.
M. Morimoto-Tomita, K. Uchimura, Z. Werb, S. Hemmerich, and S. D. Rosen (2002)
J. Biol. Chem. 277, 49175-49185
   Abstract »    Full Text »    PDF »
Slug Is a Novel Downstream Target of MyoD. TEMPORAL PROFILING IN MUSCLE REGENERATION.
P. Zhao, S. Iezzi, E. Carver, D. Dressman, T. Gridley, V. Sartorelli, and E. P. Hoffman (2002)
J. Biol. Chem. 277, 30091-30101
   Abstract »    Full Text »    PDF »
Myf5 is a direct target of long-range Shh signaling and Gli regulation for muscle specification.
M. K. Gustafsson, H. Pan, D. F. Pinney, Y. Liu, A. Lewandowski, D. J. Epstein, and C. P. Emerson Jr. (2002)
Genes & Dev. 16, 114-126
   Abstract »    Full Text »    PDF »
Wnts, Signaling and Sulfates.
S. S. Blair (2001)
Sci. STKE 2001, pe32
   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