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

Michael J Van Kanegan; Deanna G Adams; Brian E Wadzinski; Stefan Strack

doi:10.1074/jbc.M506986200

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

Journal article

Open access

Peer reviewed

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

Michael J Van Kanegan, Deanna G Adams, Brian E Wadzinski and Stefan Strack

The Journal of biological chemistry, Vol.280(43), pp.36029-36036

10/28/2005

DOI: 10.1074/jbc.M506986200

PMID: 16129692

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Abstract

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.

Okadaic Acid - pharmacology

Phosphorylation

Protein-Tyrosine Kinases - metabolism

Immunoblotting

Extracellular Signal-Regulated MAP Kinases - metabolism

PC12 Cells

MAP Kinase Signaling System

Dose-Response Relationship, Drug

RNA Interference

Fibroblast Growth Factor 2 - metabolism

Protein Phosphatase 2

Proto-Oncogene Proteins c-akt - metabolism

Dimerization

Genes, Reporter

Nerve Growth Factor - metabolism

Signal Transduction

Down-Regulation

Cells, Cultured

Gene Silencing

Rats

Epidermal Growth Factor - metabolism

Animals

Mutation

Growth Substances - metabolism

Phosphoprotein Phosphatases - chemistry

Details

Title: Subtitle: Distinct protein phosphatase 2A heterotrimers modulate growth factor signaling to extracellular signal-regulated kinases and Akt
Creators: Michael J Van Kanegan - Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA
Deanna G Adams
Brian E Wadzinski
Stefan Strack
Resource Type: Journal article
Publication Details: The Journal of biological chemistry, Vol.280(43), pp.36029-36036
DOI: 10.1074/jbc.M506986200
PMID: 16129692
NLM abbreviation: J Biol Chem
ISSN: 0021-9258
eISSN: 1083-351X
Publisher: United States
Grant note: GM51366 / NIGMS NIH HHS NS43254 / NINDS NIH HHS 5T32DK07563 / NIDDK NIH HHS GM62265 / NIGMS NIH HHS
Language: English
Date published: 10/28/2005
Academic Unit: Pathology; Iowa Neuroscience Institute; Neuroscience and Pharmacology
Record Identifier: 9984040433602771

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