Distinct protein phosphatase 2A heterotrimers modulate growth factor signaling to extracellular signal-regulated kinases and Akt.

Van Kanegan MJ, Adams DG, Wadzinski BE, Strack S
J Biol Chem. 2005 280 (43): 36029-36

PMID: 16129692 · DOI:10.1074/jbc.M506986200

A key regulator of many kinase cascades, heterotrimeric protein serine/threonine phosphatase 2A (PP2A), is composed of catalytic (C), scaffold (A), and variable regulatory subunits (B, B', B'' gene families). In neuronal PC12 cells, PP2A acts predominantly as a gatekeeper of extracellular signal-regulated kinase (ERK) activity, as shown by inducible RNA interference of the Aalpha scaffolding subunit and PP2A inhibition by okadaic acid. Although okadaic acid potentiates Akt/protein kinase B and ERK phosphorylation in response to epidermal, basic fibroblast, or nerve growth factor, silencing of Aalpha paradoxically has the opposite effect. Epidermal growth factor receptor Tyr phosphorylation was unchanged following Aalpha knockdown, suggesting that chronic Akt and ERK hyperphosphorylation leads to compensatory down-regulation of signaling molecules upstream of Ras and blunted growth factor responses. Inducible exchange of wild-type Aalpha with a mutant with selective B' subunit binding deficiency implicated PP2A/B' heterotrimers as Akt modulators. Conversely, silencing of the B-family regulatory subunits Balpha and Bdelta led to hyperactivation of ERK stimulated by constitutively active MEK1. In vitro dephosphorylation assays further support a role for Balpha and Bdelta in targeting the PP2A heterotrimer to dephosphorylate and inactivate ERKs. Thus, receptor tyrosine kinase signaling cascades leading to Akt and ERK activation are modulated by PP2A holoenzymes with distinct regulatory properties.

MeSH Terms (25)

Animals Cells, Cultured Dimerization Dose-Response Relationship, Drug Down-Regulation Epidermal Growth Factor Extracellular Signal-Regulated MAP Kinases Fibroblast Growth Factor 2 Genes, Reporter Gene Silencing Growth Substances Immunoblotting MAP Kinase Signaling System Mutation Nerve Growth Factor Okadaic Acid PC12 Cells Phosphoprotein Phosphatases Phosphorylation Protein-Tyrosine Kinases Protein Phosphatase 2 Proto-Oncogene Proteins c-akt Rats RNA Interference Signal Transduction

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