MAPKs, specially p38, are actually reported to become concerned within the inhibition of Akt signaling . Curcumin activated Erk1/2, JNK, and p38 in PC-3 cells, however the involvement of MAPKs within the inhibition of Akt/mTOR signaling by curcumin was ruled out from the failure of distinct inhibitors to restore Akt/mTOR phosphorylation . Acquiring excluded the inhibition/activation of upstream kinases in the leading inhibitory mechanism, we turned to check out the probable involvement of protein phosphatases, exclusively serine/threonine protein phosphatase seeing that the phosphorylation and dephosphorylation that regulates the components of Akt/mTOR signaling pathway primarily arise at threonine or serine. PP1 and PP2A account for that bulk of serine/threonine protein phosphatase exercise in most cells .
The PP1 inhibitor tautomycin exhibited only a really weak restoration of Akt/mTOR phosphorylation at a concentration a good deal increased than that essential for inhibition of PP1 . Then again, calyculin A fully reversed curcumin-mediated dephosphorylation of Akt, mTOR, S6, and 4E-BP1. Comparable result was observed to the expression of cyclin D1 erk inhibitors . In addition, calyculin A properly rescued the curcumin-mediated inhibition of 3H-leucine incorporation in PC-3 cells . The impact of okadaic acid was much less potent but nonetheless important, suggesting that curcumin-mediated inhibition of Akt/mTOR signaling and cell proliferation is dependent on PP2A and/or unspecified calyculin A-sensitive protein phosphatases. Curcumin is noticed to activate Src homology 2 domain-containing tyrosine phosphatase 2 in brain microglia . In a further examine, curcumin was proven to up-regulate MKP5 to repress inflammatory responses in prostate cells .
Here we noticed that curcumin also activated serine/threonine protein phosphatase action in PC-3 cells . The activities of protein phosphatases are subjected to many different ranges of regulation, even so, the precise mechanisms continues to be largely unknown . For example, PP2A holoenzyme, which includes a diversity of substrates, is composed of the core heterodimmer of catalytic dyphylline and scaffold subunits plus a broad number of regulatory subunits. The certain pursuits against particular substrates are regulated by numerous combinations of subunits and their phosphorylation or methylation status . Curcumin showed no sizeable effect to the methylation standing of C subunit ; on the other hand, it did activate serine/threnione protein phosphatases action in PC-3 cells.
Contrasting to over 300 serine/threonine kinases from the human genome, only significantly less than 30 serine/threonine phosphatases have been identified to the date , and new protein phosphatases are being identified .