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

PNAS, 13 April 2010
Vol. 107, Issue 15, p. 6882-6887
DOI: 10.1073/pnas.0910060107

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

  1. Lakshmi R. Perumalsamy,
  2. Manjula Nagala, and
  3. Apurva Sarin1
  1. National Centre for Biological Sciences, Bangalore, Karnataka 560065, India
  1. 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.

  • apoptosis
  • Bax
  • mitofusins
  • signaling

Footnotes

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

Citation:

L. R. Perumalsamy, M. Nagala, and A. Sarin, Notch-activated signaling cascade interacts with mitochondrial remodeling proteins to regulate cell survival. PNAS 107, 6882-6887 (2010).

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