{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nProtein phosphatase 6 catalytic subunit (PPP6C) is a critical serine/threonine phosphatase that governs diverse processes central to cell cycle progression and mitosis. PPP6C dephosphorylates key regulators of mitotic entry including Aurora A kinase, thereby controlling T‐loop phosphorylation and ensuring proper spindle formation and chromosome segregation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In response to DNA damage, PPP6C is recruited to damaged chromatin where it promotes dephosphorylation of γ‐H2AX, contributes to the dissolution of ionizing radiation–induced foci, and facilitates cell cycle recovery."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " In addition, by modulating the phosphorylation state of condensin I components"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "and influencing cyclin D1 levels to control the G1–S transition"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": ", PPP6C is indispensable for proper cell cycle control; its depletion in certain contexts even leads to aberrant ploidy."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond cell division, PPP6C plays pivotal roles in regulating innate immune signaling and antiviral defense. It participates in mitochondrial signalosome assembly by partnering with adaptors such as TRIM14 and WHIP, thereby facilitating dephosphorylation events that are key for RIG-I activation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " In parallel, PPP6C associates with STING and attenuates its phosphorylation; loss of this regulation enhances type I interferon production in response to cytosolic DNA."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " Moreover, PPP6C positively regulates the activity of viral RNA-dependent RNA polymerase in influenza infection through direct interactions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nPPP6C has also emerged as a significant factor in oncogenesis and hyperproliferative disorders. In melanoma, recurrent hotspot mutations in PPP6C undermine holoenzyme assembly and catalytic activity, leading to elevated Aurora A kinase activity, chromosome instability, and micronucleation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": " In hepatocellular carcinoma, microRNA‐373 targets PPP6C, reducing its expression and thereby promoting the G1/S cell cycle transition."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": " Similarly, in acute myeloid leukemia, diminished PPP6C expression due to upregulated miR‐20a‐5p fosters cell proliferation and impairs apoptosis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": " In psoriatic epidermis, NF‐κB–mediated induction of miR‐31 suppresses PPP6C, leading to enhanced keratinocyte proliferation"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": ", and in cervical cancer, aberrant PP6 signaling linked to BRCA1–ANKRD28 interactions further underscores its impact on tumor suppression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAdditional functional studies have revealed that PPP6C is integrated with regulatory subunits—such as the SAPS proteins—that confer substrate specificity and mediate its actions across cellular pathways."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "17", "end_ref": "19"}]}, {"type": "t", "text": " Moreover, PP6 regulates vesicular trafficking by dephosphorylating components of the COPII coat, facilitating ER‐to‐Golgi transport."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "20"}]}, {"type": "t", "text": " In the nervous system, PPP6C supports neurite outgrowth by dephosphorylating SIN1—a key modulator of mTORC2/Akt/CREB signaling—thus contributing to neuronal differentiation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "21"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFinally, large-scale genetic analyses have examined polymorphisms in PPP6C in the context of diseases such as celiac disease; however, these studies did not find significant associations, suggesting that the pathological impact of PPP6C is more pronounced in neoplastic and hyperproliferative as well as stress‐response settings."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "22"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Kang Zeng, Ricardo Nunes Bastos, Francis A Barr, et al. 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