A developmentally regulated, neuron-specific splice variant of the variable subunit Bbeta targets protein phosphatase 2A to mitochondria and modulates apoptosis.

Dagda RK, Zaucha JA, Wadzinski BE, Strack S
J Biol Chem. 2003 278 (27): 24976-85

PMID: 12716901 · DOI:10.1074/jbc.M302832200

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.

MeSH Terms (14)

Alternative Splicing Amino Acid Sequence Animals Apoptosis Gene Expression Regulation, Developmental Mitochondria Molecular Sequence Data Neurons Organ Specificity PC12 Cells Phosphoprotein Phosphatases Protein Phosphatase 2 Rats Signal Transduction

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