Journal
CELL BIOCHEMISTRY AND BIOPHYSICS
Volume 58, Issue 3, Pages 147-156Publisher
HUMANA PRESS INC
DOI: 10.1007/s12013-010-9101-4
Keywords
PKB; Akt; Phosphorylation; Protein phosphatase inhibitor
Funding
- European Community [QLK1-CT-2000-51184]
- Ministerio de Educacion y Ciencia [BFU2006-01088/BMC]
- Programa Ramon y Cajal [CTE/351/2004]
- U.K. Medical Research Council
- AstraZeneca
- Boehringer Ingelheim
- GlaxoSmithKline
- Merck-Serono
- Pfizer
- Medical Research Council [G9403619, MC_U127084354, G0801865] Funding Source: researchfish
- MRC [G0801865, G9403619, MC_U127084354] Funding Source: UKRI
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The protein phosphatase inhibitor calyculin A activates PKB/Akt to similar to 50% of the activity induced by insulin-like growth factor 1 (IGF1) in HeLa cells promoting an evident increased phosphorylation of Ser473 despite the apparent lack of Thr308 phosphorylation of PKB. Nevertheless, calyculin A-induced activation of PKB seems to be dependent on basal levels of Thr308 phosphorylation, since a PDK1-dependent mechanism is required for calyculin A-dependent PKB activation by using embryonic stem cells derived from PDK1 wild-type and knockout mice. Data shown suggest that calyculin A-induced phosphorylation of Ser473 was largely blocked by LY294002 and SB-203580 inhibitors, indicating that both PI3-kinase/TORC2-dependent and SAPK2/p38-dependent protein kinases contributed to phosphorylation of Ser473 in calyculin A-treated cells. Additionally, our results suggest that calyculin A blocks the IGF1-dependent Thr308 phosphorylation and activation of PKB, likely due to an enhanced Ser612 phosphorylation of insulin receptor substrate 1 (IRS1), which can be inhibitory to its activation of PI3-kinase, a requirement for PDK1-induced Thr308 phosphorylation and IGF1-dependent activation of PKB. Our data suggest that PKB activity is most dependent on the level of Ser473 phosphorylation rather than Thr308, but basal levels of Thr308 phosphorylation are a requirement. Additionally, we suggest here that calyculin A regulates the IGF1-dependent PKB activation by controlling the PI3-kinase-associated IRS1 Ser/Thr phosphorylation levels.
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