Abstract
AKT pathway has a critical role in mediating signaling transductions for cell proliferation, differentiation and survival. Previous studies have shown that AKT activation is achieved through a series of phosphorylation steps: first, AKT is phosphorylated at Thr-450 by JNK kinases to prime its activation; then, phosphoinositide-dependent kinase 1 phosphorylates AKT at Thr-308 to expose the Ser-473 residue; and finally, AKT is phosphorylated at Ser-473 by several kinases (PKD2 and others) to achieve its full activation. For its inactivation, the PH-domain containing phosphatases dephosphorylate AKT at Ser-473, and protein serine/threonine phosphatase-2A (PP-2A) dephosphorylates it at Thr-308. However, it remains unknown regarding which phosphatase dephosphorylates AKT at Thr-450 during its inactivation. In this study, we present both in vitro and in vivo evidence to show that protein serine/threonine phosphatase-1 (PP-1) is a major phosphatase that directly dephosphorylates AKT to modulate its activation. First, purified PP-1 directly dephosphorylates AKT in vitro. Second, immunoprecipitation and immunocolocalization showed that PP-1 interacts with AKT. Third, stable knock down of PP-1α or PP-1Β but not PP-1γ, PP-2Aα or PP-2AΒ by shRNA leads to enhanced phosphorylation of AKT at Thr-450. Finally, overexpression of PP-1α or PP-1Β but not PP-1γ, PP-2Aα or PP-2AΒ results in attenuated phosphorylation of AKT at Thr-450. Moreover, our results also show that dephosphorylation of AKT by PP-1 significantly modulates its functions in regulating the expression of downstream genes, promoting cell survival and modulating differentiation. These results show that PP-1 acts as a major phosphatase to dephosphorylate AKT at Thr-450 and thus modulate its functions.
Original language | English (US) |
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Pages (from-to) | 1448-1462 |
Number of pages | 15 |
Journal | Cell Death and Differentiation |
Volume | 17 |
Issue number | 9 |
DOIs | |
State | Published - Sep 2010 |
Keywords
- Akt1
- PP-1
- apoptosis
- dephosphorylation
- differentiation
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology