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Molecular and Cellular Biology, July 2008, p. 4520-4535, Vol. 28, No. 14
0270-7306/08/$08.00+0     doi:10.1128/MCB.02011-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Dynamics of RASSF1A/MOAP-1 Association with Death Receptors ^,

Caitlin J. Foley,^1, Holly Freedman,² Sheryl L. Choo,³ Christina Onyskiw,³ Nai Yang Fu,⁴ Victor C. Yu,⁴ Jack Tuszynski,² Joanne C. Pratt,¹ and Shairaz Baksh^2,3*

Franklin W. Olin College of Engineering, Olin Way, Needham, Massachusetts 02492,¹ Division of Experimental Oncology, Cross Cancer Institute, Edmonton, Alberta, Canada T6G 1Z2,² Department of Pediatrics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada T6G 2N8,³ Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos, Singapore 138673, Singapore⁴

Received 8 November 2007/ Returned for modification 24 December 2007/ Accepted 30 April 2008

RASSF1A is a tumor suppressor protein involved in death receptor-dependent apoptosis utilizing the Bax-interacting protein MOAP-1 (previously referred to as MAP-1). However, the dynamics of death receptor recruitment of RASSF1A and MOAP-1 are still not understood. We have now detailed recruitment to death receptors (tumor necrosis factor receptor 1 [TNF-R1] and TRAIL-R1/DR4) and identified domains of RASSF1A and MOAP-1 that are required for death receptor interaction. Upon TNF- stimulation, the C-terminal region of MOAP-1 associated with the death domain of TNF-R1; subsequently, RASSF1A was recruited to MOAP-1/TNF-R1 complexes. Prior to recruitment to TNF-R1/MOAP-1 complexes, RASSF1A homodimerization was lost. RASSF1A associated with the TNF-R1/MOAP-1 or TRAIL-R1/MOAP-1 complex via its N-terminal cysteine-rich (C1) domain containing a potential zinc finger binding motif. Importantly, TNF-R1 association domains on both MOAP-1 and RASSF1A were essential for death receptor-dependent apoptosis. The association of RASSF1A and MOAP-1 with death receptors involves an ordered recruitment to receptor complexes to promote cell death and inhibit tumor formation.

Published ahead of print on 12 May 2008.

Supplemental material for this article may be found at http://mcb.asm.org/.

Present address: Medical Scientist Training Program, Tufts University School of Medicine, 145 Harrison Ave., Boston, MA 02111.