Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 280, Issue 43, Pages 36029-36036Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M506986200
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Funding
- NIDDK NIH HHS [5T32DK07563] Funding Source: Medline
- NIGMS NIH HHS [GM51366, GM62265] Funding Source: Medline
- NINDS NIH HHS [NS43254] Funding Source: Medline
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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 alpha 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 alpha paradoxically has the opposite effect. Epidermal growth factor receptor Tyr phosphorylation was unchanged following A alpha 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 alpha 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 alpha and B delta led to hyperactivation of ERK stimulated by constitutively active MEK1. In vitro dephosphorylation assays further support a role for B alpha and B delta 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.
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