|
|
|
|
|
|
|
||||
| Home Help Feedback Subscriptions Archive Search Table of Contents | ||||
First published online 6 October 2004
doi: 10.1242/dev.01413
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Howard Hughes Medical Institute, Department of Genetics and Development, Columbia University College of Physicians and Surgeons, 701 West 168th Street, New York, NY 10032, USA
* Author for correspondence (e-mail: gs20{at}columbia.edu)
Accepted 20 August 2004
Recent findings suggest that Delta/Serrate/Lag2 (DSL) signals activate Notch by an unprecedented mechanism that requires the ligands to be endocytosed in signal-sending cells to activate the receptor in signal-receiving cells. Here, we show that cells devoid of Epsin, a conserved adaptor protein for Clathrin-mediated endocytosis, behave normally except that they cannot send DSL signals. Surprisingly, we find that Epsin is not required for bulk endocytosis of DSL proteins. Instead, Epsin appears to be essential for targeting DSL proteins to a special endocytic pathway that they must enter to acquire signaling activity. We present evidence that DSL proteins must be mono-ubiquitinated to be targeted by Epsin to this pathway. Furthermore, we show that the requirements for both Epsin and mono-ubiquitination can be bypassed by introducing the internalization signal that mediates endocytosis and recycling of the Low Density Lipoprotein (LDL) receptor. We propose that Epsin is essential for DSL signaling because it targets mono-ubiquitinated DSL proteins to an endocytic recycling compartment that they must enter to be converted into active ligands. Alternatively Epsin may be required to target mono-ubiquitinated DSL proteins to a particular subclass of coated pits that have special properties essential for Notch activation.
Key words: Drosophila, DSL-Notch signaling, Delta, Epsin/Liquid facets (Lqf), Endocytosis, Mono-ubiquitination
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati 
Twitter What's this?
Related articles in Development:
This article has been cited by other articles:
|
|
 |
|
  A. B. Babaoglan, K. M. O'Connor-Giles, H. Mistry, A. Schickedanz, B. A. Wilson, and J. B. Skeath Sanpodo: a context-dependent activator and inhibitor of Notch signaling during asymmetric divisions Development, December 15, 2009; 136(24): 4089 - 4098. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. A. McGill, S. E. Dho, G. Weinmaster, and C. J. McGlade Numb Regulates Post-endocytic Trafficking and Degradation of Notch1 J. Biol. Chem., September 25, 2009; 284(39): 26427 - 26438. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Chen, G. Ko, A. Zatti, G. Di Giacomo, L. Liu, E. Raiteri, E. Perucco, C. Collesi, W. Min, C. Zeiss, et al. Embryonic arrest at midgestation and disruption of Notch signaling produced by the absence of both epsin 1 and epsin 2 in mice PNAS, August 18, 2009; 106(33): 13838 - 13843. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. A. Jolly, V. Taylor, and S. A. Wood USP9X Enhances the Polarity and Self-Renewal of Embryonic Stem Cell-derived Neural Progenitors Mol. Biol. Cell, April 1, 2009; 20(7): 2015 - 2029. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. B. Butterworth, R. S. Edinger, R. A. Frizzell, and J. P. Johnson Regulation of the epithelial sodium channel by membrane trafficking Am J Physiol Renal Physiol, January 1, 2009; 296(1): F10 - F24. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. J. Brady, Y. Wen, and T. J. O'Halloran The ENTH and C-terminal domains of Dictyostelium epsin cooperate to regulate the dynamic interaction with clathrin-coated pits J. Cell Sci., October 15, 2008; 121(20): 3433 - 3444. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. R. Gordon, K. L. Arnett, and S. C. Blacklow The molecular logic of Notch signaling - a structural and biochemical perspective J. Cell Sci., October 1, 2008; 121(19): 3109 - 3119. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A.-C. Tien, A. Rajan, K. L. Schulze, H. D. Ryoo, M. Acar, H. Steller, and H. J. Bellen Ero1L, a thiol oxidase, is required for Notch signaling through cysteine bridge formation of the Lin12-Notch repeats in Drosophila melanogaster J. Cell Biol., September 22, 2008; 182(6): 1113 - 1125. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. F. Heuss, D. Ndiaye-Lobry, E. M. Six, A. Israel, and F. Logeat The intracellular region of Notch ligands Dll1 and Dll3 regulates their trafficking and signaling activity PNAS, August 12, 2008; 105(32): 11212 - 11217. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. H. Eun, S. M. L. Banks, and J. A. Fischer Auxilin is essential for Delta signaling Development, March 15, 2008; 135(6): 1089 - 1095. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Vaccari, H. Lu, R. Kanwar, M. E. Fortini, and D. Bilder Endosomal entry regulates Notch receptor activation in Drosophila melanogaster J. Cell Biol., February 25, 2008; 180(4): 755 - 762. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Koutelou, S. Sato, C. Tomomori-Sato, L. Florens, S. K. Swanson, M. P. Washburn, M. Kokkinaki, R. C. Conaway, J. W. Conaway, and N. K. Moschonas Neuralized-like 1 (Neurl1) Targeted to the Plasma Membrane by N-Myristoylation Regulates the Notch Ligand Jagged1 J. Biol. Chem., February 15, 2008; 283(7): 3846 - 3853. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Roca and R. H. Adams Regulation of vascular morphogenesis by Notch signaling Genes & Dev., October 15, 2007; 21(20): 2511 - 2524. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 U.-M. Fiuza and A. M. Arias Cell and molecular biology of Notch J. Endocrinol., September 1, 2007; 194(3): 459 - 474. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. H. Luty, D. Rodeberg, J. Parness, and Y. M. Vyas Antiparallel Segregation of Notch Components in the Immunological Synapse Directs Reciprocal Signaling in Allogeneic Th:DC Conjugates J. Immunol., July 15, 2007; 179(2): 819 - 829. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. M. Traub and G. L. Lukacs Decoding ubiquitin sorting signals for clathrin-dependent endocytosis by CLASPs J. Cell Sci., February 15, 2007; 120(4): 543 - 553. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Ing, A. Shteiman-Kotler, M. Castelli, P. Henry, Y. Pak, B. Stewart, G. L. Boulianne, and D. Rotin Regulation of Commissureless by the Ubiquitin Ligase DNedd4 Is Required for Neuromuscular Synaptogenesis in Drosophila melanogaster Mol. Cell. Biol., January 15, 2007; 27(2): 481 - 496. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Commisso and G. L. Boulianne The NHR1 Domain of Neuralized Binds Delta and Mediates Delta Trafficking and Notch Signaling Mol. Biol. Cell, January 1, 2007; 18(1): 1 - 13. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. L. Parks, J. R. Stout, S. B. Shepard, K. M. Klueg, A. A. Dos Santos, T. R. Parody, M. Vaskova, and M. A. T. Muskavitch Structure-Function Analysis of Delta Trafficking, Receptor Binding and Signaling in Drosophila Genetics, December 1, 2006; 174(4): 1947 - 1961. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Song, B.-K. Koo, K.-J. Yoon, M.-J. Yoon, K.-W. Yoo, H.-T. Kim, H.-J. Oh, Y.-Y. Kim, J.-K. Han, C.-H. Kim, et al. Neuralized-2 Regulates a Notch Ligand in Cooperation with Mind Bomb-1 J. Biol. Chem., November 24, 2006; 281(47): 36391 - 36400. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. M. Millard and S. A. Wood Riding the DUBway: regulation of protein trafficking by deubiquitylating enzymes J. Cell Biol., May 22, 2006; 173(4): 463 - 468. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Wang, L. M. Traub, K. M. Weixel, M. J. Hawryluk, N. Shah, R. S. Edinger, C. J. Perry, L. Kester, M. B. Butterworth, K. W. Peters, et al. Clathrin-mediated Endocytosis of the Epithelial Sodium Channel: ROLE OF EPSIN J. Biol. Chem., May 19, 2006; 281(20): 14129 - 14135. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. J. Hagedorn, J. L. Bayraktar, V. R. Kandachar, T. Bai, D. M. Englert, and H. C. Chang Drosophila melanogaster auxilin regulates the internalization of Delta to control activity of the Notch signaling pathway J. Cell Biol., May 8, 2006; 173(3): 443 - 452. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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. Presenilin-Based Genetic Screens in Drosophila melanogaster Identify Novel Notch Pathway Modifiers Genetics, April 1, 2006; 172(4): 2309 - 2324. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. S. Campos, L. Decker, V. Taylor, and W. Skarnes Notch, Epidermal Growth Factor Receptor, and beta1-Integrin Pathways Are Coordinated in Neural Stem Cells J. Biol. Chem., February 24, 2006; 281(8): 5300 - 5309. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Katic, L. G. Vallier, and I. Greenwald New Positive Regulators of lin-12 Activity in Caenorhabditis elegans Include the BRE-5/Brainiac Glycosphingolipid Biosynthesis Enzyme Genetics, December 1, 2005; 171(4): 1605 - 1615. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Pitsouli and C. Delidakis The interplay between DSL proteins and ubiquitin ligases in Notch signaling Development, September 15, 2005; 132(18): 4041 - 4050. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Roegiers, L. Y. Jan, and Y. N. Jan Regulation of Membrane Localization of Sanpodo by lethal giant larvae and neuralized in Asymmetrically Dividing Cells of Drosophila Sensory Organs Mol. Biol. Cell, August 1, 2005; 16(8): 3480 - 3487. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Wang and G. Struhl Distinct roles for Mind bomb, Neuralized and Epsin in mediating DSL endocytosis and signaling in Drosophila Development, June 15, 2005; 132(12): 2883 - 2894. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. C. Lai, F. Roegiers, X. Qin, Y. N. Jan, and G. M. Rubin The ubiquitin ligase Drosophila Mind bomb promotes Notch signaling by regulating the localization and activity of Serrate and Delta Development, May 15, 2005; 132(10): 2319 - 2332. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Le Borgne, A. Bardin, and F. Schweisguth The roles of receptor and ligand endocytosis in regulating Notch signaling Development, April 15, 2005; 132(8): 1751 - 1762. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Chen and P. De Camilli From the Cover: The association of epsin with ubiquitinated cargo along the endocytic pathway is negatively regulated by its interaction with clathrin PNAS, February 22, 2005; 102(8): 2766 - 2771. [Abstract] [Full Text] [PDF]
|
|
