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PNAS 107 (15): 6882-6887

Copyright © 2010 by the National Academy of Sciences.


BIOLOGICAL SCIENCES / CELL BIOLOGY

Notch-activated signaling cascade interacts with mitochondrial remodeling proteins to regulate cell survival

Lakshmi R. Perumalsamy, Manjula Nagala, and Apurva Sarin1

National Centre for Biological Sciences, Bangalore, Karnataka 560065, India

Edited by Anjana Rao, Harvard Medical School, Immune Disease Institute, Children's Hospital Boston, Boston, MA, and approved January 29, 2010 (received for review September 3, 2009)

Abstract: Survival of differentiated cells is one of several processes regulated by Notch activity, although the general principles underlying this function remain to be characterized. Here, we probe the mechanism underlying Notch-mediated survival, building on emerging evidence that apoptotic responses coordinated by specialized intermediates converge on mitochondria, identifying a core event in death pathways. The Bcl-2 family protein Bax is one such intermediate, which in a unifying response to diverse apoptotic stimuli nucleates multiprotein assemblies on mitochondria, committing cells to irrevocable damage. Using Bax as the prototype stimulus, we analyze Notch signaling for potential interactions with mitochondria, probe intrinsic properties of the Notch receptor, and describe key intermediates in the Notch-activated signaling cascade. Ligand-dependent processing was necessary to generate the Notch intracellular domain (NIC) although signaling was independent of canonical interactions with nuclear factors. Notably, antiapoptotic activity was recapitulated by NIC recombinants, localized outside the nucleus, and compromised by enforced nuclear sequestration. NIC signaled via the kinase Akt to prevent the loss of mitochondrial function, contiguity, and consequent nuclear damage, outcomes critically depend on mitochondrial remodeling proteins Mitofusins-(Mfn)-1 and 2. Thus, the NIC-Akt-Mfn signaling cascade identifies a pathway regulating cell-survival, independent of canonical functions associated with NIC activity.

Key Words: apoptosis • Bax • mitofusins • signaling


Author contributions: L.R.P. and A.S. designed research; L.R.P. and M.N. performed research; L.R.P. contributed new reagents/analytic tools; L.R.P., M.N., and A.S. analyzed data; and L.R.P. and A.S. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at www.pnas.org/cgi/content/full/0910060107/DCSupplemental.

1To whom correspondence may be addressed. E-mail: sarina{at}ncbs.res.in or apurva.sarin{at}gmail.com.


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