Editors' ChoiceApoptosis

Dephosphorylation to Die For

Science Signaling  30 Nov 2010:
Vol. 3, Issue 150, pp. ec364
DOI: 10.1126/scisignal.3150ec364

A key decision point in cells destined to undergo cell death or apoptosis is the activation of the Bak and Bax proteins. Conformational changes in these proteins lead to permeabilization of the mitochondrial outer membrane, release of cytochrome C, and the cascade of events that commit the cell to death. Bak and Bax are regulated by interactions with members of the Bcl-2 family of proteins, but Fox et al. now provide evidence for an additional layer of regulation of Bak through tyrosine phosphorylation. The authors identified a specific tyrosine residue, Y108, on Bak that is normally phosphorylated in healthy cells. Treatment of mouse embryo fibroblasts with a DNA-damaging agent to induce apoptosis caused dephosphorylation of Y108 on Bak. Inhibiting such dephosphorylation prevented the conformational change in Bak that is required for its activation. Cells expressing a Bak protein in which Y108 was converted to alanine grew comparably to control cells but were more sensitive to stimuli that cause cell death. Thus, dephosphorylation of Bak appears to be necessary but not sufficient to cause Bak activation. Fox et al. used siRNA screening to identify three protein tyrosine phosphatases—PTPN2, PTPN5, and PTPN23—that appeared to contribute to Bak activation after DNA damage. PTPN5 was the most effective and is itself regulated by phosphorylation mediated by the mitogen-activated protein (MAP) kinases ERK1 and ERK2. MAP kinase activation generally promotes cell survival, and activity of ERK1 and ERK2 was transiently decreased in cells treated with a DNA-damaging agent. This corresponded with a decrease in phosphorylation of PTPN5 and of Y108 in Bak. Pharmacological inhibition of MAP kinase signaling also resulted in decreased phosphorylation of Y108 in Bak. Thus, the authors propose that Bak serves as a point of integration of MAP kinase signaling with that of other pathways that influence association of Bak with pro-apoptotic proteins. Also, the molecular settings of this system suggest that by default cells are programmed to survive (rather than to die, as previously suggested) and require multiple positive signals to initiate apoptosis.

J. L. Fox, F. Ismail, A. Azad, N. Ternette, S. Leverrier, M. J. Edelmann, B. M. Kessler, I. M. Leigh, S. Jackson, A. Storey, Tyrosine dephosphorylation is required for Bak activation in apoptosis. EMBO J. 29, 3853–3868 (2010). [PubMed]