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J. Biol. Chem., Vol. 281, Issue 15, 10089-10097, April 14, 2006

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Microfibrillar Proteins MAGP-1 and MAGP-2 Induce Notch1 Extracellular Domain Dissociation and Receptor Activation^*

Alison Miyamoto, Rhiana Lau, Patrick W. Hein, J. Michael Shipley, and Gerry Weinmaster¹

From the Department of Biological Chemistry, David Geffen School of Medicine at UCLA, Los Angeles, California 90095 and Department of Medicine, Division of Pulmonary and Critical Care Medicine, Washington University, St. Louis, Missouri 63110

Unlike most receptors, Notch serves as both the receiver and direct transducer of signaling events. Activation can be mediated by one of five membrane-bound ligands of either the Delta-like (-1, -2, -4) or Jagged/Serrate (-1, -2) families. Alternatively, dissociation of the Notch heterodimer with consequent activation can also be mediated experimentally by calcium chelators or by mutations that destabilize the Notch1 heterodimer, such as in the human disease T cell acute lymphoblastic leukemia. Here we show that MAGP-2, a protein present on microfibrils, can also interact with the EGF-like repeats of Notch1. Co-expression of MAGP-2 with Notch1 leads to both cell surface release of the Notch1 extracellular domain and subsequent activation of Notch signaling. Moreover, we demonstrate that the C-terminal domain of MAGP-2 is required for binding and activation of Notch1. Based on the high level of homology, we predicted and further showed that MAGP-1 can also bind to Notch1, cause the release of the extracellular domain, and activate signaling. Notch1 extracellular domain release induced by MAGP-2 is dependent on formation of the Notch1 heterodimer by a furin-like cleavage, but does not require the subsequent ADAM metalloprotease cleavage necessary for production of the Notch signaling fragment. Together these results demonstrate for the first time that the microfibrillar proteins MAGP-1 and MAGP-2 can function outside of their role in elastic fibers to activate a cellular signaling pathway.

Received for publication, January 11, 2006 , and in revised form, February 9, 2006.

^* This work was supported by National Institutes of Health Grant NS31885 and STOP CANCER (to G. W.). 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.

¹ To whom correspondence should be addressed: Dept. of Biological Chemistry, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095. Tel.: 310-206-9446; Fax: 310-206-5272; E-mail: gweinmaster{at}mednet.ucla.edu.

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