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J. Biol. Chem., Vol. 280, Issue 43, 36029-36036, October 28, 2005
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Distinct Protein Phosphatase 2A Heterotrimers Modulate Growth Factor Signaling to Extracellular Signal-regulated Kinases and Akt*
1
From the
Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242 and the Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee 37232
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 A
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 A paradoxically has the opposite effect. Epidermal growth factor receptor Tyr phosphorylation was unchanged following A 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 A with a mutant with selective B' subunit binding deficiency implicated PP2A/B' heterotrimers as Akt modulators. Conversely, silencing of the B-family regulatory subunits B and B
led to hyperactivation of ERK stimulated by constitutively active MEK1. In vitro dephosphorylation assays further support a role for B and B 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.
Received for publication, June 27, 2005 , and in revised form, August 4, 2005.
* This work was supported by National Institute of Health Grants NS43254 (to S. S.) and GM51366 and GM62265 (to B. E. W), a predoctoral fellowship from the Pharmaceutical Research and Manufacturers of America (PhRMA) foundation (to M. J. V.), and National Institutes of Health Training Grant 5T32DK07563 (to D. G. A). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 To whom correspondence should be addressed: Dept. of Pharmacology, University of Iowa Carver College of Medicine, 2-432 BSB, 51 Newton Rd., Iowa City, IA 52242. Tel.: 319-384-4439; Fax: 319-335-8930; E-mail: stefan-strack{at}uiowa.edu.
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