Signal Transduction

Getting Apoptosis Started

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Science  17 Dec 2010:
Vol. 330, Issue 6011, pp. 1589
DOI: 10.1126/science.330.6011.1589-c
CREDIT: FOX ET AL., EMBO J. 29, 3853 (2010)

Activation of the Bak and Bax proteins in response to apoptotic stimuli initiates the cascade of events that commit the cell to death. Bak and Bax activation requires a conformational change followed by multimerization, and now Fox et al. provide evidence for an additional layer of regulation. The authors identified a specific tyrosine residue, Y108, on Bak that is phosphorylated in healthy human cells but was dephosphorylated during apoptosis. Dephosphorylation of Bak led to a conformational change and was necessary but not sufficient to cause Bak activation. A siRNA screen identified the protein tyrosine phosphatase PTPN5 as a major contributor to Bak activation in response to apoptotic stimuli. PTPN5 was regulated by the mitogen-activated protein (MAP) kinases ERK1 and ERK2. MAP kinase activation generally promotes cell survival, and MAP kinase activity was transiently decreased in cells treated with an apoptotic stimulus. This corresponded with increased dephosphorylation of Y108 by PTPN5. Thus, Bak may act as a point of integration of MAP kinase signaling with other pathways that influence the association of Bak with proapoptotic proteins. These results also suggest that by default, cells are programmed to survive and require multiple positive signals to initiate apoptosis.

EMBO J. 29, 3853 (2010).

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