Calcium Depletion Dissociates and Activates Heterodimeric Notch Receptors

doi:10.1128/MCB.20.5.1825-1835.2000

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Molecular and Cellular Biology, March 2000, p. 1825-1835, Vol. 20, No. 5
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Calcium Depletion Dissociates and Activates Heterodimeric Notch Receptors

Matthew D. Rand,¹ Lisa M. Grimm,¹ Spyros Artavanis-Tsakonas,¹ Vytas Patriub,² Stephen C. Blacklow,² Jeffrey Sklar,² and Jon C. Aster²^,^*

Massachusetts General Hospital Cancer Center, Department of Cell Biology, Harvard Medical School, Charlestown, Massachusetts 02129,¹ and Division of Molecular Oncology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115²

Received 1 June 1999/Returned for modification 21 July 1999/Accepted 17 November 1999

Notch receptors participate in a highly conserved signaling pathway that regulates morphogenesis in multicellular animals.Maturation of Notch receptors requires the proteolytic cleavageof a single precursor polypeptide to produce a heterodimer composedof a ligand-binding extracellular domain (N^EC) and a single-pass transmembrane signaling domain (N^TM). Notch signaling has been correlated with additional ligand-inducedproteolytic cleavages, as well as with nuclear translocation ofthe intracellular portion of N^TM (N^ICD). In the current work, we show that the N^EC and N^TM subunits of Drosophila Notch and human Notch1 (hN1) interactnoncovalently. N^EC-N^TM interaction was disrupted by 0.1% sodium dodecyl sulfate or divalentcation chelators such as EDTA, and stabilized by millimolar Ca²⁺. Deletion of the Ca²⁺-binding Lin12-Notch (LN) repeats from the N^EC subunit resulted in spontaneous shedding of N^EC into conditioned medium, implying that the LN repeats are importantin maintaining the interaction of N^EC and N^TM. The functional consequences of EDTA-induced N^EC dissociation were studied by using hN1-expressing NIH 3T3 cells.Treatment of these cells for 10 to 15 min with 0.5 to 10 mM EDTAresulted in the rapid shedding of N^EC, the transient appearance of a polypeptide of the expected sizeof N^ICD, increased intranuclear anti-Notch1 staining, and the transientactivation of an Notch-sensitive reporter gene. EDTA treatmentof HeLa cells expressing endogenous Notch1 also stimulated reportergene activity to a degree equivalent to that resulting from exposureof the cells to the ligand Delta1. These findings indicate thatreceptor activation can occur as a consequence of N^EC dissociation, which relieves inhibition of the intrinsicallyactive N^TMsubunit.

^* Corresponding author. Mailing address: Division of Molecular Oncology, Department of Pathology, Brigham & Women's Hospital,Harvard Medical School, 75 Francis St., Boston, MA 02115. Phone:(617) 732-7483. Fax: (617) 732-7449. E-mail: jaster{at}rics.bwh.harvard.edu.

Molecular and Cellular Biology, March 2000, p. 1825-1835, Vol. 20, No. 5
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

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