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Abstract Akt is a protein serine/threonine kinase that is involved in the regulation of diverse cellular processes. Phosphorylation of Akt at regulatory residues Thr-308 and Ser-473 leads to its full activation.

The protein phosphatase 2A (PP2A) has long been known to negatively regulate Akt activity. The PP2A holoenzyme consists of the structural subunit (A), catalytic subunit (C), and a variable regulatory subunit (B).

Here we report the identification of the specific B regulatory subunit that targets the PP2A holoenzyme to Akt. We found endogenous association of PP2A AB55C holoenzymes with Akt by co-immunoprecipitation analyses in pro-lymphoid FL5.12 cells. Akt was shown to associate with ectopically expressed B55α subunit in NIH3T3 cells.

The direct interaction between B55α subunit and Akt was confirmed using in vitro pulldown analyses. Intriguingly, we found that overexpression of B55α subunit significantly impaired phosphorylation at Thr-308, but to a lesser extent at Ser-473 of Akt in both FL5.12 and NIH3T3 cells.

Concomitantly, phosphorylation of a subset of Akt substrates, including FoxO3a, was substantially decreased by B55α overexpression in these cells. Silencing of B55α expression markedly increased phosphorylation at Thr-308 but not at Ser-473 in both FL5.12 cells and NIH3T3 cells. Consistently, PP2A AB55αC holoenzymes preferentially dephosphorylated phospho-Thr-308 rather than phospho-Ser-473 in in vitro dephosphorylation assays. Furthermore, B55α overexpression retarded proliferation of NIH3T3 cells, and knockdown of B55α expression increased survival of FL5.12 cells upon interleukin-3 deprivation. Together, our data demonstrate that B55α-dependent targeting of the PP2A holoenzyme to Akt selectively regulates Akt phosphorylation at Thr-308 to regulate cell proliferation and survival. Akt/protein kinase B (PKB), also named RAC kinase, is involved in the regulation of diverse cellular processes, including glucose metabolism, cell growth, cell proliferation, angiogenesis, and apoptosis (,–). Deregulated Akt activity has been linked to the formation of various human malignancies such as gastric adenocarcinoma, ovarian cancer, breast cancer, and thyroid cancer (,, ).

Akt is a crucial signal transducer downstream of phosphatidylinositide 3′-OH kinase (PI3K) that is activated upon ligand and receptor engagement on the cell surface. The Akt family consists of three major isoforms, Akt1/PKBα, Akt2/PKBβ, and Akt3/PKBγ, that have conserved functional domains, including an N-terminal pleckstrin homology domain, a central kinase domain, and a C-terminal regulatory domain. Recruitment of Akt to the plasma membrane upon activation of PI3K results in a conformational change, and phosphorylation of Thr-308 and Ser-473 after membrane recruitment of Akt leads to full activation of Akt (, ). Akt activation is tightly controlled by counteraction of phosphatases, and tensin homologue deleted on chromosome 10 (PTEN) (), protein phosphatase 2A (PP2A) (–), and pleckstrin homology domain leucine-rich repeat protein phosphatase (PHLPP) () was reported to regulate Akt activity.

It has long been known that PP2A negatively regulates Akt activity in various systems. PP2A holoenzymes consist of a dimeric core enzyme, which includes the catalytic subunit C, the structural subunit A, and a variable regulatory subunit B (–). Multiple families and isoforms of the regulatory subunit B increase the diversity of the PP2A holoenzymes. There are at least four subfamilies of the regulatory subunit, including B (B55 or PR55) (–), B′ (B56 or PR61) (, ), B″ (PR72) (), and B′′′ (PR93/PR110) (). It is thought that the diverse regulatory subunits dictate substrate specificity and subcellular localization of PP2A. Signaling modules composed of PP2A and variable kinases have been identified and are believed to increase the fidelity of signaling transduction process. The kinases that have been found to interact with PP2A include calcium-calmodulin-dependent protein kinase IV (), p70 S6 kinase (, ), p21-activated kinases (), p38 kinase (), casein kinase II (), IκB kinases (, ), mitogen-activated protein kinase (MAPK) (, ), and Akt (, –).

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