{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPPP2CA—the α‐isoform of protein phosphatase 2A (PP2A)—is a critical serine/threonine phosphatase that plays multifaceted roles in regulating cell cycle progression, mitotic exit, transcriptional fidelity, and autophagy. For example, PPP2CA-containing PP2A holoenzymes (such as PP2A–B55α) are essential for promoting postmitotic spindle breakdown and reassembly of interphase structures, acting downstream of Cdk1 inactivation (1."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In parallel, stimulation‐induced dephosphorylation of the autophagy kinase ULK1 by PP2A–B55α serves to trigger ULK1‐dependent autophagy following mTORC1 inactivation (2."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " Moreover, PPP2CA is discussed in the context of PP2A holoenzyme biogenesis and regulation, where its assembly with diverse regulatory subunits determines substrate specificity and subcellular targeting (3."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " In cardiac myocytes, complexes such as mAKAP–PP2A dephosphorylate targets like PDE4D3, thereby dynamically modulating localized cAMP signaling (4"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ", while PP2A associated with the Integrator complex dephosphorylates the RNA polymerase II C‐terminal domain and transcription elongation factor Spt5 to attenuate productive transcription (5."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " In addition, PP2A‐mediated dephosphorylation of the pocket proteins, including Rb, underlines its role in fine‐tuning cell cycle progression (6."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn stress and survival signaling, PPP2CA exerts key regulatory functions that critically influence cellular fate. Oxidative stress (e.g. H₂O₂ exposure) can inhibit PP2A activity through glutathionylation mechanisms, thereby altering the phosphorylation status of multiple substrates (7."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " PP2A complexes containing regulatory subunits (for instance, B56α) modulate the phosphorylation of anti‐apoptotic targets such as Bcl2, linking phosphatase activity to ceramide‐induced apoptosis (8."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " In certain cancers, activation of kinase‐mediated receptors including EphB3 promotes the assembly of a signal complex with PP2A that ultimately dampens Akt signaling and cell migration, emphasizing a tumor‐suppressive role (9."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " In neuronal and vascular contexts, recruitment of PP2A via the UNC5H2 dependence receptor activates DAPk to drive apoptosis (10."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": " In neurodegenerative settings, the interplay between GSK‑3β and PP2A contributes to the regulation of tau phosphorylation, while loss of PP2A activity is implicated in SNCA accumulation in Parkinson’s disease models (11"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "; 12."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": " Besides, binding of EB1 to Aurora‑B shields the kinase from PP2A‐mediated dephosphorylation thereby sustaining its activity during mitosis (13."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": " Additional studies reveal that PP2A is involved in tumor suppressor checkpoints activated upon SPRY2 deficiency (14"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": "and that PP2A modulates stress‐activated MAPK pathways in neutrophils (15."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": " In hepatocellular carcinoma models, nilotinib’s autophagy‐inducing effects are linked to regulation of AMPK phosphorylation by PP2A (16"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": ", while aberrant PP2A activity in T cells contributes to dysregulated MEK/ERK signaling in systemic lupus erythematosus (17."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "17"}]}, {"type": "t", "text": " In non‑small‑cell lung cancer, overexpression of SET oncoprotein perturbs PP2A function and is linked to enhanced Akt activity and tumor progression (18."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}]}, {"type": "t", "text": " Furthermore, in cancer stem-like cells, activation of protective pathways and NF‑κB signaling is associated with altered PP2A functions (19"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "19"}]}, {"type": "t", "text": ", and PP2A regulation is central to responses under UVB/IL‑1 stimulation where its inhibition results in sustained IKKβ activity (20."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "20"}]}, {"type": "t", "text": " PP2A’s role in maintaining epithelial integrity is further illustrated by its recruitment to tight junctions upon acetaldehyde exposure causing occludin dephosphorylation (21"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "21"}]}, {"type": "t", "text": ", and by its modulation of Akt phosphorylation in a nucleotide occupancy–dependent manner (22."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "22"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nThe regulation of PPP2CA expression and activity is itself intricately controlled by epigenetic and protein–protein interactions that have implications for disease. Differential expression studies reveal that while the PPP2CA (Aα) isoform predominates over Aβ in most tissues, subtle changes in PP2A subunit composition affect substrate engagement (23."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "23"}]}, {"type": "t", "text": " In T cells from lupus patients, hypomethylation of the PP2A catalytic subunit promoter and decreased DNMT1 expression have been linked to its overexpression, directly impacting immune function (24"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "24"}]}, {"type": "t", "text": "; 40."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "25"}]}, {"type": "t", "text": " Similarly, microRNA‑155 downregulates PP2A mRNA in juvenile systemic lupus erythematosus, influencing IL‑2 production (25."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "26"}]}, {"type": "t", "text": " In cancer cells, disrupted PP2A activity through a Tgase‑2/PP2A/JNK axis promotes epithelial–mesenchymal transition by enhancing N‑cadherin expression (26"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "27"}]}, {"type": "t", "text": ", while deregulation of PP2A is linked to altered PAK1 and TAK1 signaling under stress conditions (27"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "28"}]}, {"type": "t", "text": "; 28."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "29"}]}, {"type": "t", "text": " Moreover, hyperosmotic stress studies show that PP2A governs focal adhesion dynamics and p38 MAPK activity (29"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "30"}]}, {"type": "t", "text": ", and in cardiac muscle, PP2A modulates myofilament Ca²⁺ sensitivity by controlling troponin I phosphorylation (30."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "31"}]}, {"type": "t", "text": " In the nervous system, PP2A dephosphorylates ATXN1 at Ser‑776—a modification that influences interactions with splicing factors (31"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "32"}]}, {"type": "t", "text": "—and its downregulation has been implicated in the androgen‑independent growth of prostate cancer (32."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "33"}]}, {"type": "t", "text": " In fibrotic lung disease, an aberrant PP2A/HDAC4 axis suppresses miR‑29, promoting excessive type I collagen deposition (33."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "34"}]}, {"type": "t", "text": " Furthermore, binding partners such as α4 modulate PP2A stability and substrate access (34"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "35"}]}, {"type": "t", "text": ", and emerging chemical inhibitors like LB‑100—targeting both PP2A and related phosphatases—highlight the therapeutic potential of modulating PPP2CA activity in malignancies such as glioblastoma (35"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "36"}]}, {"type": "t", "text": "; 36"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "37"}]}, {"type": "t", "text": "; 38."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "38"}]}, {"type": "t", "text": " In addition, oncoproteins such as CIP2A inhibit PP2A function to stabilize oncogenic drivers (37"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "39"}]}, {"type": "t", "text": ", and in lung cancer models, a Tgase‑2/PP2A/JNK signaling cascade further links PP2A activity to cellular plasticity during epithelial–mesenchymal transition (39."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "40"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Michael H A Schmitz, Michael Held, Veerle Janssens, et al. 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