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

• DOI: 10.1073/pnas.0910060107
• Publication Date: 2010-03-26T01:28:39Z
• Authors: Lakshmi R. Peruma...; Manjula Nagala; Apurva Sarin
• Keywords: Hes3 signaling axis

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