![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Vol. 18, Issue 1, 176-188, January 2007
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
*Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, NY 10021; Biochemical Institute, Christian-Albrechts University, D-24098 Kiel, Germany; Department of Orthopedic Surgery, Keio University, School of Medicine, Tokyo, 160-8582 Japan; Cambridge Institute for Medical Research, Cambridge CB2 2XY, United Kingdom; ||Department for Human Genetics, K.U. Leuven and Flanders Interuniversity Institute for Biotechnology (VIB-4), 3000 Leuven, Belgium; and ¶Departments of Medicine and of Physiology and Biophysics, Weill Medical College of Cornell University, New York, NY 10021
Submitted January 6, 2006;
Revised September 25, 2006;
Accepted October 19, 2006
Monitoring Editor: Ben Margolis
Signaling via the epidermal growth factor receptor (EGFR), which has critical roles in development and diseases such as cancer, is regulated by proteolytic shedding of its membrane-tethered ligands. Sheddases for EGFR-ligands are therefore key signaling switches in the EGFR pathway. Here, we determined which ADAMs (a disintegrin and metalloprotease) can shed various EGFR-ligands, and we analyzed the regulation of EGFR-ligand shedding by two commonly used stimuli, phorbol esters and calcium influx. Phorbol esters predominantly activate ADAM17, thereby triggering a burst of shedding of EGFR-ligands from a late secretory pathway compartment. Calcium influx stimulates ADAM10, requiring its cytoplasmic domain. However, calcium influx-stimulated shedding of transforming growth factor 
and amphiregulin does not require ADAM17, even though ADAM17 is essential for phorbol ester-stimulated shedding of these EGFR-ligands. This study provides new insight into the machinery responsible for EGFR-ligand release and thus EGFR signaling and demonstrates that dysregulated EGFR-ligand shedding may be caused by increased expression of constitutively active sheddases or activation of different sheddases by distinct stimuli.
The online version of this contains supplemental material at MBC Online (http://www.molbiolcell.org). This article was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E06-01-0014) on November 1, 2006.
Address correspondence to: Carl P. Blobel (blobelc{at}hss.edu)
This article has been cited by other articles:
|
|
 |
|
  H. P. Jia, D. C. Look, P. Tan, L. Shi, M. Hickey, L. Gakhar, M. C. Chappell, C. Wohlford-Lenane, and P. B. McCray Jr Ectodomain shedding of angiotensin converting enzyme 2 in human airway epithelia Am J Physiol Lung Cell Mol Physiol, July 1, 2009; 297(1): L84 - L96. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Horiuchi, H. Morioka, H. Takaishi, H. Akiyama, C. P. Blobel, and Y. Toyama Ectodomain Shedding of FLT3 Ligand Is Mediated by TNF-{alpha} Converting Enzyme J. Immunol., June 15, 2009; 182(12): 7408 - 7414. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Guaiquil, S. Swendeman, T. Yoshida, S. Chavala, P. A. Campochiaro, and C. P. Blobel ADAM9 Is Involved in Pathological Retinal Neovascularization Mol. Cell. Biol., May 15, 2009; 29(10): 2694 - 2703. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. M. Le Gall, P. Bobe, K. Reiss, K. Horiuchi, X.-D. Niu, D. Lundell, D. R. Gibb, D. Conrad, P. Saftig, and C. P. Blobel ADAMs 10 and 17 Represent Differentially Regulated Components of a General Shedding Machinery for Membrane Proteins Such as Transforming Growth Factor {alpha}, L-Selectin, and Tumor Necrosis Factor {alpha} Mol. Biol. Cell, March 15, 2009; 20(6): 1785 - 1794. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. J. Duffy, E. McKiernan, N. O'Donovan, and P. M. McGowan Role of ADAMs in Cancer Formation and Progression Clin. Cancer Res., February 15, 2009; 15(4): 1140 - 1144. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Boutet, S. Aguera-Gonzalez, S. Atkinson, C. J. Pennington, D. R. Edwards, G. Murphy, H. T. Reyburn, and M. Vales-Gomez Cutting Edge: The Metalloproteinase ADAM17/TNF-{alpha}-Converting Enzyme Regulates Proteolytic Shedding of the MHC Class I-Related Chain B Protein J. Immunol., January 1, 2009; 182(1): 49 - 53. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Herrlich, E. Klinman, J. Fu, C. Sadegh, and H. Lodish Ectodomain cleavage of the EGF ligands HB-EGF, neuregulin1-{beta}, and TGF-{alpha} is specifically triggered by different stimuli and involves different PKC isoenzymes FASEB J, December 1, 2008; 22(12): 4281 - 4295. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Arduise, T. Abache, L. Li, M. Billard, A. Chabanon, A. Ludwig, P. Mauduit, C. Boucheix, E. Rubinstein, and F. Le Naour Tetraspanins Regulate ADAM10-Mediated Cleavage of TNF-{alpha} and Epidermal Growth Factor J. Immunol., November 15, 2008; 181(10): 7002 - 7013. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. P. Sorensen, R. R. Vives, C. Manetopoulos, R. Albrechtsen, M. C. Lydolph, J. Jacobsen, J. R. Couchman, and U. M. Wewer Heparan Sulfate Regulates ADAM12 through a Molecular Switch Mechanism J. Biol. Chem., November 14, 2008; 283(46): 31920 - 31932. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Swendeman, K. Mendelson, G. Weskamp, K. Horiuchi, U. Deutsch, P. Scherle, A. Hooper, S. Rafii, and C. P. Blobel VEGF-A Stimulates ADAM17-Dependent Shedding of VEGFR2 and Crosstalk Between VEGFR2 and ERK Signaling Circ. Res., October 24, 2008; 103(9): 916 - 918. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Waldhauer, D. Goehlsdorf, F. Gieseke, T. Weinschenk, M. Wittenbrink, A. Ludwig, S. Stevanovic, H.-G. Rammensee, and A. Steinle Tumor-Associated MICA Is Shed by ADAM Proteases Cancer Res., August 1, 2008; 68(15): 6368 - 6376. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Zhuang, G. R. Kinsey, K. Rasbach, and R. G. Schnellmann Heparin-binding epidermal growth factor and Src family kinases in proliferation of renal epithelial cells Am J Physiol Renal Physiol, March 1, 2008; 294(3): F459 - F468. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Ali and V. Knauper Phorbol Ester-induced Shedding of the Prostate Cancer Marker Transmembrane Protein with Epidermal Growth Factor and Two Follistatin Motifs 2 Is Mediated by the Disintegrin and Metalloproteinase-17 J. Biol. Chem., December 28, 2007; 282(52): 37378 - 37388. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. L. Moss, M. Bomar, Q. Liu, H. Sage, P. Dempsey, P. M. Lenhart, P. A. Gillispie, A. Stoeck, D. Wildeboer, J. W. Bartsch, et al. The ADAM10 Prodomain Is a Specific Inhibitor of ADAM10 Proteolytic Activity and Inhibits Cellular Shedding Events J. Biol. Chem., December 7, 2007; 282(49): 35712 - 35721. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Horiuchi, T. Miyamoto, H. Takaishi, A. Hakozaki, N. Kosaki, Y. Miyauchi, M. Furukawa, J. Takito, H. Kaneko, K. Matsuzaki, et al. Cell Surface Colony-Stimulating Factor 1 Can Be Cleaved by TNF-{alpha} Converting Enzyme or Endocytosed in a Clathrin-Dependent Manner J. Immunol., November 15, 2007; 179(10): 6715 - 6724. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Kawaguchi, K. Horiuchi, J. D. Becherer, Y. Toyama, P. Besmer, and C. P. Blobel Different ADAMs have distinct influences on Kit ligand processing: phorbol-ester-stimulated ectodomain shedding of Kitl1 by ADAM17 is reduced by ADAM19 J. Cell Sci., March 15, 2007; 120(6): 943 - 952. [Abstract] [Full Text] [PDF]
|
|
