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J. Biol. Chem., Vol. 283, Issue 12, 8046-8054, March 21, 2008

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 283/12/8046    most recent M800170200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Li, K. Articles by Zhou, B.-B. S. PubMed PubMed Citation Articles by Li, K. Articles by Zhou, B.-B. S. Social Bookmarking                      What's this?

Modulation of Notch Signaling by Antibodies Specific for the Extracellular Negative Regulatory Region of NOTCH3^*

Kang Li¹, Yucheng Li, Wenjuan Wu, Wendy R. Gordon, David W. Chang, Mason Lu, Shane Scoggin, Tihui Fu, Long Vien, Gavin Histen, Ji Zheng, Rachel Martin-Hollister, Thomas Duensing, Sanjaya Singh, Stephen C. Blacklow², Zhengbin Yao, Jon C. Aster², and Bin-Bing S. Zhou³

From the Tanox, Incorporated, Houston, Texas 77025 and the Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115

The Notch pathway regulates the development of many tissues and cell types and is involved in a variety of human diseases, making it an attractive potential therapeutic target. This promise has been limited by the absence of potent inhibitors or agonists that are specific for individual human Notch receptors (NOTCH1-4). Using an unbiased functional screening, we identified monoclonal antibodies that specifically inhibit or induce activating proteolytic cleavages in NOTCH3. Remarkably, the most potent inhibitory and activating antibodies bind to overlapping epitopes within a juxtamembrane negative regulatory region that protects NOTCH3 from proteolysis and activation in its resting autoinhibited state. The inhibitory antibodies revert phenotypes conveyed on 293T cells by NOTCH3 signaling, such as increased cellular proliferation, survival, and motility, whereas the activating antibody mimics some of the effects of ligand-induced Notch activation. These findings provide insights into the mechanisms of Notch autoinhibition and activation and pave the way for the further development of specific antibody-based modulators of the Notch receptors, which are likely to be of utility in a wide range of experimental and therapeutic settings.

Received for publication, January 8, 2008

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S4.

² Supported by grants from the National Institutes of Health.

¹ To whom correspondence may be addressed: Pfizer-La Jolla, 10628 Science Center Dr., San Diego, CA 92121. Tel.: 858-622-7694; Fax: 858-526-4450; E-mail: kyfli{at}yahoo.com.

³ To whom correspondence may be addressed: Wyeth Research, 401 N. Middletown Road, Pearl River, NY 10965. Tel.: 845-602-1924; Fax: 845-602-5557; E-mail: binbing_s_zhou{at}yahoo.com.

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