{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRecent studies have established that p21‑activated kinase 3 (PAK3) is a pivotal regulator of actin remodeling underlying synaptic formation, plasticity, and the consolidation of long‐term memory. In neurons, PAK3 governs dendritic spine morphology and synaptic strength, processes that are essential for learning and cognitive function. Disruption of PAK3 activity—whether by loss‐of‐function mutations, dominant‐negative forms, or its misregulation through upstream modulators—results in abnormal spine architecture, impaired bidirectional synaptic plasticity, and consequent deficits in hippocampal‑dependent memory and behavior. Such studies underscore that precise PAK3 signaling is necessary not only for synapse formation and maturation but also for proper cortical interneuron migration and social memory, further implicating its role in neurodevelopment and cognition."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn endocrine and neoplastic contexts, PAK3 has been shown to drive critical differentiation programs. In pancreatic islet progenitors, for example, PAK3 acts downstream of neurogenin3 to promote cell cycle exit and β‑cell maturation, while in thymic carcinoids, its overexpression is linked to enhanced migratory and invasive properties mediated by JNK signaling. These findings indicate that proper regulation of PAK3 signaling is equally essential outside the nervous system for maintaining regulated cell proliferation and differentiation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAdditional studies have extended the role of PAK3 to other cell types and stress responses. In hematopoietic stem and progenitor cells, for instance, PAK3 (together with other group I PAKs) is necessary for proper cell adhesion, migration, and activation of ERK signaling, while in osteoblasts PAK3 influences the cytoskeletal architecture and cellular motility necessary for bone remodeling. Moreover, alterations in PAK3 signaling following cranial irradiation have implicated its pathway in the maintenance of cognitive functions under stress conditions. Collectively, these studies reveal that PAK3 serves as a multidimensional modulator of cytoskeletal dynamics and cell architecture across diverse tissues."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "14", "end_ref": "19"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAlthough none of the studies summarized above directly investigated TEX26‑AS1, the extraordinary breadth of PAK3’s impact across neuronal, endocrine, and other cellular systems suggests that TEX26‑AS1—a long noncoding antisense transcript—may be an important regulatory element modulating PAK3 expression or function. By analogy, TEX26‑AS1 could influence pathways governing synapse formation, cell cycle exit, and migration, thereby contributing indirectly to the cognitive and developmental processes in which PAK3 plays a central role. Future focused investigations are needed to elucidate whether TEX26‑AS1 functions as a regulatory switch for PAK3-dependent signaling and to clarify its potential roles in both physiologic and pathologic contexts.\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Mansuo L Hayashi, Se-Young Choi, B S Shankaranarayana Rao, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "The mental retardation protein PAK3 contributes to synapse formation and plasticity in hippocampus."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neurosci (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1523/JNEUROSCI.2931-04.2004"}], "href": "https://doi.org/10.1523/JNEUROSCI.2931-04.2004"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15574732"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15574732"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Jinsong Meng, Yanghong Meng, Amanda Hanna, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "p21-Activated kinases 1 and 3 control brain size through coordinating neuronal complexity and synaptic properties."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Biol (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/MCB.00969-10"}], "href": "https://doi.org/10.1128/MCB.00969-10"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21115725"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21115725"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Aline Dubos, Gaelle Combeau, Yann Bernardinelli, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "The intellectual disability PAK3 R67C mutation impacts cognitive functions and adult hippocampal neurogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddz296"}], "href": "https://doi.org/10.1093/hmg/ddz296"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31943058"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31943058"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Susan Zhou, Zhengping Jia "}, {"type": "b", "children": [{"type": "t", "text": "Disruption of PAK3 Signaling in Social Interaction Induced cFos Positive Cells Impairs Social Recognition Memory."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cells (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3390/cells10113010"}], "href": "https://doi.org/10.3390/cells10113010"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34831234"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34831234"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Lucie Viou, Melody Atkins, Véronique Rousseau, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PAK3 activation promotes the tangential to radial migration switch of cortical interneurons by increasing leading process dynamics and disrupting cell polarity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Psychiatry (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41380-024-02483-y"}], "href": "https://doi.org/10.1038/s41380-024-02483-y"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38454080"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38454080"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Julie Piccand, Aline Meunier, Carole Merle, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Pak3 promotes cell cycle exit and differentiation of β-cells in the embryonic pancreas and is necessary to maintain glucose homeostasis in adult mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Diabetes (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.2337/db13-0384"}], "href": "https://doi.org/10.2337/db13-0384"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24163148"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24163148"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Patricia Kreis, Véronique Rousseau, Emmanuel Thévenot, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The four mammalian splice variants encoded by the p21-activated kinase 3 gene have different biological properties."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neurochem (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1471-4159.2008.05474.x"}], "href": "https://doi.org/10.1111/j.1471-4159.2008.05474.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18507705"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18507705"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Veronique Rousseau, Olivier Goupille, Nathalie Morin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A new constitutively active brain PAK3 isoform displays modified specificities toward Rac and Cdc42 GTPases."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M207251200"}], "href": "https://doi.org/10.1074/jbc.M207251200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12464619"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12464619"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Rui-xin Liu, Wei-qing Wang, Lei Ye, et al. "}, {"type": "b", "children": [{"type": "t", "text": "p21-activated kinase 3 is overexpressed in thymic neuroendocrine tumors (carcinoids) with ectopic ACTH syndrome and participates in cell migration."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Endocrine (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s12020-010-9324-6"}], "href": "https://doi.org/10.1007/s12020-010-9324-6"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20960100"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20960100"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Majistor Raj Luxman Maglorius Renkilaraj, Lucas Baudouin, Claire M Wells, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The intellectual disability protein PAK3 regulates oligodendrocyte precursor cell differentiation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neurobiol Dis (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.nbd.2016.12.004"}], "href": "https://doi.org/10.1016/j.nbd.2016.12.004"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27940202"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27940202"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Kazunori Kageyama, Satoru Sakihara, Toshihiro Suda "}, {"type": "b", "children": [{"type": "t", "text": "Regulation and role of p21-activated kinase 3 by corticotropin-releasing factor in mouse pituitary."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Regul Pept (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.regpep.2008.10.003"}], "href": "https://doi.org/10.1016/j.regpep.2008.10.003"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18940205"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18940205"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Haksoo Lee, Hyunkoo Kang, Changjong Moon, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PAK3 downregulation induces cognitive impairment following cranial irradiation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Elife (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.7554/eLife.89221"}], "href": "https://doi.org/10.7554/eLife.89221"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38131292"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38131292"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Simona Bolamperti, Hiroaki Saito, Sarah Heerdmann, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Tgif1-deficiency impairs cytoskeletal architecture in osteoblasts by activating PAK3 signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Elife (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.7554/eLife.94265"}], "href": "https://doi.org/10.7554/eLife.94265"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38661167"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38661167"}]}]}]}