title: "Licensed to kill": tyrosine dephosphorylation and Bak activation.
abstract: The genomes of multi-cellular organisms are under constant assault from a host of environmental agents. The efficient elimination of cells harbouring damage is essential to avoid the accumulation of deleterious changes that may promote tumorigenesis. Consequently, a complex and elaborate series of damage responses have evolved to either ensure that correct repair of the DNA has been carried out, or alternatively, to initiate programmes that result in the ablation of the damaged cell. Apoptosis is recognized as both a fast an efficient way of disposing of damaged or unwanted cells before they accumulate changes that may result in the acquisition of neoplastic autonomy. The mitochondrial apoptotic pathway relies upon two effector proteins of the Bcl2 family, Bax and Bak, that when activated form pores in the outer mitochondrial membrane that release cytochrome c and other apoptogenic factors. We have recently shown that the initiation of Bak activation is controlled by dephosphorylation. In particular, we found that a specific tyrosine dephosphorylation was required for Bak activation to proceed, and that tyrosine phosphatases may serve to integrate apoptotic signals that culminate in Bak dephosphorylation. Here, we discuss these findings and present additional data underlining the importance of dephosphorylation in the Bak activation process, and how the modulation of Bak phosphorylation status may be modified to enhance cell killing.
authors.affiliation: Department of Molecular Oncology, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
authors.forename: Joanna
authors.initials: J
authors.lastname: Fox
authors.forename: Abul
authors.initials: A
authors.lastname: Azad
authors.forename: Ferina
authors.initials: F
authors.lastname: Ismail
authors.forename: Alan
authors.initials: A
authors.lastname: Storey
mesh_terms: D017209:Apoptosis / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D004249:DNA Damage / Q000235:genetics; D004260:DNA Repair / Q000235:genetics; D006801:Humans; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction; D014443:Tyrosine / Q000737:chemistry / Q000378:metabolism*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000235:genetics / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D014443:Tyrosine