Modulation of Notch signaling by antibodies specific for the extracellular negative regulatory region of NOTCH3

The Journal of Biological Chemistry
Kang LiBin-Bing S Zhou

Abstract

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.

References

Sep 28, 1995·Nature·S JarriaultA Israel
Feb 20, 1996·Proceedings of the National Academy of Sciences of the United States of America·R KopanJ S Nye
Jul 1, 1997·Nature Genetics·T OdaS C Chandrasekharappa
Jul 8, 1998·Proceedings of the National Academy of Sciences of the United States of America·F LogeatA Israël
Apr 21, 2001·The Journal of Immunology : Official Journal of the American Association of Immunologists·C LuT A Springer
Mar 14, 2002·Proceedings of the National Academy of Sciences of the United States of America·Diana BellaviaIsabella Screpanti
Jul 12, 2002·Journal of Neuroscience Research·Carol HicksGerry Weinmaster
Jun 26, 2003·Nucleic Acids Research·Torsten SchwedeManuel C Peitsch
Jun 3, 2004·Nature Reviews. Molecular Cell Biology·Raphael Kopan, Ma Xenia G Ilagan
Nov 17, 2004·Genes & Development·Valérie DomengaAnne Joutel
Dec 2, 2004·Acta Crystallographica. Section D, Biological Crystallography·Paul Emsley, Kevin Cowtan
May 12, 2005·Current Opinion in Immunology·Margaret J DallmanJonathan R Lamb
Jun 17, 2005·Nature·Silvia FreSpyros Artavanis-Tsakonas
Jul 19, 2005·Nature·Vidu GargDeepak Srivastava
Jun 17, 2006·Cancer Research·Joon T ParkTian-Li Wang
Aug 22, 2006·Nature Reviews. Molecular Cell Biology·Sarah J Bray
Feb 8, 2007·Proceedings of the National Academy of Sciences of the United States of America·Yunsun NamStephen C Blacklow
Apr 3, 2007·Nature Structural & Molecular Biology·Wendy R GordonStephen C Blacklow

❮ Previous
Next ❯

Citations

May 21, 2013·Acta Pharmacologica Sinica·Ke ChenJi-long Chen
Mar 11, 2011·Nature Biotechnology·Andrew R M BradburyJohn McCafferty
May 23, 2009·Nature Reviews. Cancer·Robert C BastGordon B Mills
Oct 2, 2009·Nature Reviews. Drug Discovery·Bin-Bing S ZhouPeter B Dirks
Sep 2, 2008·Oncogene·P RizzoL Miele
Sep 2, 2008·Oncogene·D BellaviaI Screpanti
Oct 19, 2011·Proceedings of the National Academy of Sciences of the United States of America·Nicholas J WangRaymond J Cho
Sep 4, 2009·The Journal of Biological Chemistry·Geert van TeteringMarc Vooijs
Jan 23, 2013·The Journal of Biological Chemistry·Pat WhitemanPenny A Handford
Jun 10, 2010·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Antonio PannutiLucio Miele
Dec 21, 2010·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Karisa C SchreckCharles G Eberhart
Dec 18, 2010·Blood·Cynthia Guidos
May 17, 2013·Cell Communication and Signaling : CCS·William A SandsHelen Wheadon
Nov 20, 2012·BMC Medicine·Rossella RotaFranco Locatelli
Jun 16, 2011·Breast Cancer Research : BCR·Jianxun HanJoan Allalunis-Turner
Sep 19, 2008·Journal of Cell Science·Wendy R GordonStephen C Blacklow
Dec 23, 2011·Archives of Pathology & Laboratory Medicine·Olga PozdnyakovaScott J Rodig
May 2, 2014·Nature Reviews. Drug Discovery·Emma R Andersson, Urban Lendahl
Mar 6, 2013·Pharmacology & Therapeutics·Ingrid Espinoza, Lucio Miele
Sep 11, 2014·Wiener medizinische Wochenschrift·Klaus Geissler
Apr 16, 2010·Expert Opinion on Therapeutic Targets·Elodie Ristorcelli, Dominique Lombardo
Jan 14, 2012·Expert Opinion on Therapeutic Targets·Pamela Jo HarrisClaudio Dansky Ullmann
Jun 19, 2013·Expert Opinion on Drug Discovery·Joshua C Curtin
Sep 12, 2009·Expert Opinion on Biological Therapy·Ashley R Sandy, Ivan Maillard
Aug 13, 2015·International Journal of Cancer. Journal International Du Cancer·Kaitlyn E VinsonGeorge Sigounas
Feb 18, 2016·Stem Cells International·Ahmet AcarKeith Brennan
Jul 22, 2011·Trends in Immunology·Ute Koch, Freddy Radtke
Apr 7, 2009·Advances in Enzyme Regulation·Paola RizzoLucio Miele
Sep 7, 2012·The Journal of Pathology·Maria Dolores Sanchez-Niño, Alberto Ortiz
Apr 16, 2016·Indian Journal of Surgical Oncology·Neha Deshpande, Annapoorni Rangarajan
Apr 7, 2010·Biochemical Pharmacology·Ling YinZhao-Jun Liu
Dec 7, 2013·Journal of Hepatology·Carola Maria Morell, Mario Strazzabosco
Jun 12, 2013·Journal of Molecular Biology·Kittichoat TiyanontStephen C Blacklow
Jul 10, 2012·Seminars in Cancer Biology·Katia Sampieri, Riccardo Fodde
Feb 9, 2012·Seminars in Cell & Developmental Biology·Casper Groth, Mark E Fortini
Feb 7, 2012·Seminars in Cell & Developmental Biology·Abdiwahab A MusseGerry Weinmaster
Apr 22, 2009·Cell·Raphael Kopan, Maria Xenia G Ilagan

❮ Previous
Next ❯

Related Concepts

Related Feeds

ASBMB Publications

The American Society for Biochemistry and Molecular Biology (ASBMB) includes the Journal of Biological Chemistry, Molecular & Cellular Proteomics, and the Journal of Lipid Research. Discover the latest research from ASBMB here.

Antibody Specificity

Antibodies produced by B cells are highly specific for antigen as a result of random gene recombination and somatic hypermutation and affinity maturation. As the main effector of the humoral immune system, antibodies can neutralize foreign cells. Find the latest research on antibody specificity here.