cAMP regulation of protein phosphatases PP1 and PP2A in brain

Abstract

Normal functioning of the brain is dependent upon a complex web of communication between numerous cell types. Within neuronal networks, the faithful transmission of information between neurons relies on an equally complex organization of inter- and intra-cellular signaling systems that act to modulate protein activity. In particular, post-translational modifications (PTMs) are responsible for regulating protein activity in response to neurochemical signaling. The key second messenger, cyclic adenosine 3’,5’- monophosphate (cAMP), regulates one of the most ubiquitous and influential PTMs, phosphorylation. While cAMP is canonically viewed as regulating the addition of phosphate groups through its activation of cAMP-dependent protein kinases, it plays an equally critical role in regulating removal of phosphate through indirect control of protein phosphatase activity. This dichotomy of regulation by cAMP places it as one of the key regulators of protein activity in response to neuronal signal transduction throughout the brain. In this review we focus on the role of cAMP in regulation of the serine/threonine phosphatases protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A) and the relevance of control of PP1 and PP2A to regulation of brain function and behavior.

The Cell Cycle Checkpoint System MAST(L)-ENSA/ARPP19-PP2A is Targeted by cAMP/PKA and cGMP/PKG in Anucleate Human Platelets

“…PKA phosphorylation of ARPP16 could interfere with the extent of PP2A inhibition by pS46 ARPP16 • PKA could phosphorylate and inhibit the ARPP16 S46 kinase MAST3 • Forskolin-stimulated PKA could activate PP2A by phosphorylation of PP2A B56δ [42] resulting in reduced S46 ARPP16 phosphorylation Some of these effects may perhaps be specific for brain, as was recently reviewed [55]. However, in our phosphoproteomic analysis, we clearly detected PP2A B56δ S573 phosphorylation in human platelets (Table 2) in response to iloprost (cAMP system) and riociguat (cGMP system), which we were able to confirm using phospho-specific antibodies ( Figure S4).…”

“…In contrast, OA binds directly to and inhibits all PP2A catalytic subunits, independent of the regulatory B subunits, and also inhibits structurally closely related serine/threonine protein phosphatases such as PP4/PP6 [62]. S67-/S62-phosphorylated ENSA/ARPP19 are thought to achieve their inhibitory effects via direct binding to a limited number of PP2A regulatory B-subunits (B55/B56 subfamily) [31,33,48,55]. However, there are very few studies available on the regulation of mammalian/human PP2A by the ENSA/ARPP family, and none for platelets and other blood cells.…”

“…In contrast to protein kinases and their substrates/inhibitors, no reliable consensus sequence for serine/threonine protein phosphatases including PP2A have been established to date [26] in spite of considerable research efforts [65,70]. Nevertheless, multiple PP2A substrates have been studied and established within various processes such as intracellular signalling, cell cycle regulation, cell morphology and development as well as in brain function [23,55,71,72]. Because of the possible contribution of PP2A substrates to cell growth, cell survival and tumour suppression, phosphoproteins of the MAP kinase pathway and PI3K/Akt signalling have been particularly well studied [72][73][74].…”

The M-phase regulatory phosphatase PP2A-B55δ opposes protein kinase A on Arpp19 to initiate meiotic division

“…The two mutually antagonistic enzymes, PKA and PP2A-B55δ, work simultaneously, with the action of PP2A-B55δ being swamped by PKA. This contrasts with other systems in which PKA plays a critical role in phosphate removal by regulating protein phosphatase activities 47 , for example by phosphorylating B56 and activating PP2A-B56δ in human brain 48 Remarkably, both Arpp19 sites important for the control of meiosis resumption, S109 and S67, are dephosphorylated by a unique phosphatase, PP2A-B55δ. The function of Arpp19 phosphorylation at S67 in converting this protein into a PP2A-B55δ inhibitor is well documented, whereas the action of S109 phosphorylation of Arpp19 in ensuring the prophase arrest remains unknown.…”

Piezo1 activation attenuates thrombin-induced blebbing in breast cancer cells

“…6). PP1/PP2A phosphatases can be activated by PKA 54,55 ; however, as mentioned above, confinement-induced Piezo1 activation has been associated with reduced PKA activity 27 . Amongst the PP1/PP2A phosphatases the B"/PR72 regulatory subunit is reported to be regulated by Ca 2+ , with two EF-hand motifs that when Ca 2+ bound activate PP2A phosphatases [56][57][58] .…”