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Molecular and Cellular Biology, November 2004, p. 9265-9273, Vol. 24, No. 21
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.21.9265-9273.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Notch Subunit Heterodimerization and Prevention of Ligand-Independent Proteolytic Activation Depend, Respectively, on a Novel Domain and the LNR Repeats

Cheryll Sanchez-Irizarry,1 Andrea C. Carpenter,2 Andrew P. Weng,1 Warren S. Pear,2 Jon C. Aster,1 and Stephen C. Blacklow1*

Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts,1 Department of Pathology and Laboratory Medicine, Institute for Medicine and Engineering, The Abramson Family Cancer Research Institute, University of Pennsylvania Medical School, Philadelphia, Pennsylvania2

Received 7 May 2004/ Returned for modification 15 June 2004/ Accepted 30 July 2004

Notch proteins are transmembrane receptors that participate in a highly conserved signaling pathway that regulates morphogenesis in metazoans. Newly synthesized Notch receptors are proteolytically cleaved during transit to the cell surface, creating heterodimeric mature receptors comprising noncovalently associated extracellular (NEC) and transmembrane (NTM) subunits. Ligand binding activates Notch by inducing two successive proteolytic cleavages, catalyzed by metalloproteases and gamma-secretase, respectively, that permit the intracellular portion of NTM to translocate to the nucleus and activate transcription of target genes. Prior work has shown that the presence of NEC prevents ligand-independent activation of NTM, but the mechanisms involved are poorly understood. Here, we define the roles of two regions at the C-terminal end of NEC that participate in maintaining the integrity of resting Notch receptors through distinct mechanisms. The first region, a hydrophobic, previously uncharacterized portion of NEC, is sufficient to form stable complexes with the extracellular portion of NTM. The second region, consisting of the three Lin12/Notch repeats, is not needed for heterodimerization but acts to protect NTM from ligand-independent cleavage by metalloproteases. Together, these two contiguous regions of NEC impose crucial restraints that prevent premature Notch receptor activation.

* Corresponding author. Mailing address: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, 77 Ave. Louis Pasteur, Boston, MA 02115. Phone: (617) 525-4413. Fax: (617) 525-4414. E-mail: sblacklow{at}rics.bwh.harvard.edu.

Molecular and Cellular Biology, November 2004, p. 9265-9273, Vol. 24, No. 21
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.21.9265-9273.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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