Survival factor-mediated BAD phosphorylation raises the mitochondrial threshold for apoptosis

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Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death
09:18

Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death

Published on: December 27, 2016

Sandeep Robert Datta1, Ann M Ranger, Michael Z Lin

  • 1Division of Neuroscience, Children's Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.

Developmental Cell
|November 15, 2002
PubMed

Insights

Growth factor signaling prevents cell death by inactivating the proapoptotic protein BAD through phosphorylation. This mechanism protects cells from apoptosis by regulating mitochondrial cytochrome c release.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Biochemistry

Background:

  • Growth factors inhibit apoptosis, a process linked to the phosphorylation and inactivation of proapoptotic proteins like BAD.
  • The precise physiological mechanisms by which growth factors block cell death remain incompletely understood.
  • BAD is a key BCL-2 family member regulating the intrinsic apoptotic pathway.

Purpose of the Study:

  • To investigate the role of BAD phosphorylation in cell survival.
  • To elucidate the in vivo contribution of BAD inactivation to growth factor-mediated cell death suppression.
  • To understand how survival kinases utilize BAD phosphorylation to block apoptosis.

Main Methods:

  • Generation of mice with specific point mutations in the BAD gene to abolish phosphorylation at key sites.
  • Assessment of cell survival and apoptotic signaling in mutant mice exposed to apoptotic stimuli.
  • Analysis of cytochrome c release from mitochondria as a measure of apoptosis induction.

Main Results:

  • BAD phosphorylation was demonstrated to protect cells against apoptotic stimuli.
  • Phosphorylation of BAD attenuates death pathway signaling by increasing the threshold for mitochondrial cytochrome c release.
  • Mutant mice lacking BAD phosphorylation sites exhibited increased sensitivity to apoptotic insults.

Conclusions:

  • Endogenous BAD phosphorylation plays a critical role in promoting cell survival.
  • BAD phosphorylation acts as a key molecular switch, raising the mitochondrial threshold for apoptosis induction.
  • This study elucidates a significant mechanism by which survival kinases prevent apoptosis in vivo.

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