To be or not to be: PP2A as a dual player in CNS functions, its role in neurodegeneration, and its interaction with brain insulin signaling

Abstract

Accumulating evidence has reached the consensus that the balance of phosphorylation state of signaling molecules is a pivotal point in the regulation of cell signaling. Therefore, characterizing elements (kinases-phosphatases) in the phosphorylation balance are at great importance. However, the role of phosphatase enzymes is less investigated than kinase enzymes. PP2A is a member of serine/threonine protein phosphatase that its imbalance has been reported in neurodegenerative diseases. Therefore, we reviewed the superfamily of phosphatases and more specifically PP2A, its regulation, and physiological functions participate in CNS. Thereafter, we discussed the latest findings about PP2A dysregulation in Alzheimer and Parkinson diseases and possible interplay between this phosphatase and insulin signaling pathways. Finally, activating/inhibitory modulators for PP2A activity as well as experimental methods for PP2A study have been reviewed.

Keywords: Alzheimer disease; Brain; Insulin; Insulin resistance; Parkinson disease; Protein phosphatase 2A.

Fig. 1

Schematic diagram showing protein phosphatases categorization. Ser/Thr phosphatases serine/threonine phosphatases, PTPs protein tyrosine phosphatases, DSPs dual-specific protein phosphatase, PPPs phosphoprotein phosphatases, PPMs metal metal-dependent protein phosphatases, Asp-based aspartate-based, Cdc cell division cycle, LMWPTP low-molecular-mass protein tyrosine phosphatase, EYA eyes absent, A-DSP atypical DSP, MKP mitogen-activated protein kinases (MAPK) phosphatase, PRLs phosphatases of regenerating liver

Fig. 2

Schematic diagram showing different PP2A regulatory molecules. P phosphate group, Me methyl group, PME-1 protein phosphatase methylesterase-1, LCMT leucine Carboxyl Methyltransferase 1, PTPA protein phosphatase 2 phosphatase activator/phosphotyrosyl phosphatase activator, TIPRL-1 target of rapamycin signaling pathway regulator-like, IGBP1 or α-4 immunoglobulin-α-binding protein 1, CDK cyclin-dependent kinase, RTK src-like or receptor tyrosine kinase, I1 and I2 (SET) inhibitor-1 and -2 of PP2A. Inhibitory pathways are represented by dash lines and activatory pathways are shown by solid lines

Fig. 3

Schematic diagram showing the interplay among PP2A, kinases and status of AD-related proteins. Aβ amyloid beta, JNK c-Jun N-terminal kinases, cdk5 Cyclin-dependent kinase 5, Bcl-2 B-cell lymphoma 2, LTP long-term potential, PKC protein kinase C, MAPK mitogen-activated protein kinase, PP2A protein phosphatase 2A, GSK-3β Glycogen synthase kinase 3β, NFT neurofibrillary tangle. Inhibitory pathways are represented by dash lines and activatory pathways are shown by solid lines

Fig. 4

Schematic diagram showing PP2A and insulin signaling pathway interaction. This figure shows that PP2A activity could either promote tau phosphorylation or its dephosphorylation. PP2A protein phosphatase 2A, JNK c-Jun N-terminal kinase, mTOR mammalian target of rapamycin, IRS insulin receptor substrate, GSK-3β glycogen synthase kinase 3β. Inhibitory pathways are represented by dash lines and activatory pathways are shown by solid lines

Fig. 5

Schematic diagram showing PP2A targeting compounds. P phosphate group, Me methyl group, CIP2A cancerous inhibitor of PP2A, SMAPs small molecule activators of PP2A. Inhibitory compounds are presented in dash line squares and activatory compounds are presented in solid squares