A developmentally regulated, neuron-specific splice variant of the variable subunit Bbeta targets protein phosphatase 2A to mitochondria and modulates apoptosis.
Heterotrimeric protein phosphatase 2A (PP2A) is a major Ser/Thr phosphatase composed of catalytic, structural, and regulatory subunits. Here, we characterize Bbeta2, a novel splice variant of the neuronal Bbeta regulatory subunit with a unique N-terminal tail. Bbeta2 is expressed predominantly in forebrain areas, and PP2A holoenzymes containing Bbeta2 are about 10-fold less abundant than those containing the Bbeta1 (previously Bbeta) isoform. Bbeta2 mRNA is dramatically induced postnatally and in response to neuronal differentiation of a hippocampal progenitor cell line. The divergent N terminus of Bbeta2 does not affect phosphatase activity but encodes a subcellular targeting signal. Bbeta2, but not Bbeta1 or an N-terminal truncation mutant, colocalizes with mitochondria in neuronal PC12 cells. Moreover, the Bbeta2 N-terminal tail is sufficient to target green fluorescent protein to this organelle. Inducible or transient expression of Bbeta2, but neither Bbeta1, Bgamma, nor a Bbeta2 mutant defective in holoenzyme formation, accelerates apoptosis in response to growth factor deprivation. Thus, alternative splicing of a mitochondrial localization signal generates a PP2A holoenzyme involved in neuronal survival signaling.
Dagda
Ruben K
RK
Department of. Pharmacology, University of Iowa Carver College of Medicine, Iowa City 52242, USA.
Zaucha
Julie A
JA
Wadzinski
Brian E
BE
Strack
Stefan
S
D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental; D008928:Mitochondria / Q000473:pathology / Q000502:physiology; D008969:Molecular Sequence Data; D009474:Neurons / Q000473:pathology / Q000502:physiology*; D009928:Organ Specificity; D016716:PC12 Cells; D010749:Phosphoprotein Phosphatases / Q000235:genetics*; D054648:Protein Phosphatase 2; D051381:Rats; D015398:Signal Transduction / Q000235:genetics
D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2