{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSEPTIN2 is a conserved GTP‐binding member of the septin family that functions as a central building block for higher‐order cytoskeletal assemblies. High‐resolution structural studies have revealed that its extended G domain engages in conserved nucleotide‐dependent interactions with septin partners such as SEPT6 and SEPT7, forming a universal bipolar hetero‐oligomeric rod that underpins filament assembly. In addition, detailed structural analyses have uncovered alternative coiled‐coil arrangements that may contribute to the dynamic versatility of SEPTIN2 within these complexes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAt the cellular level, SEPTIN2 plays a pivotal role in organizing the actin and microtubule cytoskeletons. In epithelial cells, SEPTIN2-containing fibers align with polyglutamylated microtubule tracks to facilitate vesicle transport and the maintenance of polarized membrane domains, while its loss—often in conjunction with SEPT6 and SEPT7 depletion—leads to disruption of stress fibers and loss of cell polarity. Moreover, SEPTIN2 is incorporated into septin complexes present in primary cilia, where it contributes to ciliary architecture, and it also acts as a scaffold during host–pathogen interactions by nucleating actin coats around pathogen‐associated vacuoles and by promoting receptor–ligand interactions that facilitate bacterial entry."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its cytoskeletal roles, SEPTIN2 is directly involved in mitochondrial dynamics. Its physical binding to the fission mediator Drp1 ensures efficient mitochondrial constriction and subsequent fission, underlining a critical role in organelle quality control and cellular energy homeostasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nDysregulation of SEPTIN2 has emerged as a significant factor in oncogenesis across multiple tissue types. In hepatocellular carcinoma, for example, overexpression and phosphorylation of SEPTIN2 by casein kinase 2 promote aberrant cell proliferation and polarity loss"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": ", while in biliary tract cancer, elevated SEPTIN2 expression enhances invasion and tumor growth by modulating matrix metalloproteinases and other downstream effectors."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": " Its oncogenic roles extend to breast and glioblastoma cancers"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": ", and SEPTIN2 has been identified as the fusion partner of MLL in a subset of acute myeloid leukemias."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": " In gastric cancer, SEPTIN2 is instrumental in stabilizing the receptor tyrosine kinase ErbB2 at the plasma membrane by shielding it from ubiquitylation and lysosomal degradation"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "17"}]}, {"type": "t", "text": ", and in prostate cancer, deregulated expression of SEPTIN2—mediated via noncoding RNA pathways—fosters cell proliferation through activation of the JAK–STAT3 pathway."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "19"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nSEPTIN2 function is further modulated by small molecules and its propensity to aggregate. Computational docking studies indicate that inhibitors such as forchlorfenuron can bind to the nucleotide‐binding pocket of SEPTIN2, locking it into a conformation that mimics its GTP‐bound state and thereby altering filament dynamics."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "20"}]}, {"type": "t", "text": " In addition, an imbalance in septin stoichiometry can lead to the formation of amyloid‐like aggregates of SEPTIN2, suggesting that its overabundance may contribute to pathological inclusions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "21"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFinally, in normal physiology, SEPTIN2 supports the maintenance of epithelial barrier function. In airway epithelial cells, enhanced membrane localization of SEPTIN2 is associated with reorganization of the cortical actin network, which modulates paracellular permeability and ensures proper spatial segregation of membrane receptors."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "22"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Minhajuddin Sirajuddin, Marian Farkasovsky, Florian Hauer, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structural insight into filament formation by mammalian septins."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nature (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nature06052"}], "href": "https://doi.org/10.1038/nature06052"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17637674"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17637674"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Claudia Low, Ian G Macara "}, {"type": "b", "children": [{"type": "t", "text": "Structural analysis of septin 2, 6, and 7 complexes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M605179200"}], "href": "https://doi.org/10.1074/jbc.M605179200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16914550"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16914550"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Deborah C Mendonça, Samuel L Guimarães, Humberto D'Muniz Pereira, et al. "}, {"type": "b", "children": [{"type": "t", "text": "An atomic model for the human septin hexamer by cryo-EM."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Mol Biol (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jmb.2021.167096"}], "href": "https://doi.org/10.1016/j.jmb.2021.167096"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34116125"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34116125"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Diego A Leonardo, Italo A Cavini, Fernanda A Sala, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Orientational Ambiguity in Septin Coiled Coils and its Structural Basis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Mol Biol (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jmb.2021.166889"}], "href": "https://doi.org/10.1016/j.jmb.2021.166889"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33639214"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33639214"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Brandon E Kremer, Laura A Adang, Ian G Macara "}, {"type": "b", "children": [{"type": "t", "text": "Septins regulate actin organization and cell-cycle arrest through nuclear accumulation of NCK mediated by SOCS7."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cell.2007.06.053"}], "href": "https://doi.org/10.1016/j.cell.2007.06.053"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17803907"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17803907"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Elias T Spiliotis, Stephen J Hunt, Qicong Hu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Epithelial polarity requires septin coupling of vesicle transport to polyglutamylated microtubules."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Biol (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1083/jcb.200710039"}], "href": "https://doi.org/10.1083/jcb.200710039"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18209106"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18209106"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Rania Ghossoub, Qicong Hu, Marion Failler, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Septins 2, 7 and 9 and MAP4 colocalize along the axoneme in the primary cilium and control ciliary length."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Sci (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1242/jcs.111377"}], "href": "https://doi.org/10.1242/jcs.111377"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23572511"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23572511"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Serge Mostowy, Sébastien Janel, Claire Forestier, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A role for septins in the interaction between the Listeria monocytogenes INVASION PROTEIN InlB and the Met receptor."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biophys J (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bpj.2011.02.040"}], "href": "https://doi.org/10.1016/j.bpj.2011.02.040"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21504731"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21504731"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Larisa Volceanov, Katharina Herbst, Martin Biniossek, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Septins arrange F-actin-containing fibers on the Chlamydia trachomatis inclusion and are required for normal release of the inclusion by extrusion."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "mBio (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/mBio.01802-14"}], "href": "https://doi.org/10.1128/mBio.01802-14"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25293760"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25293760"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Alessandro Pagliuso, To Nam Tham, Julia K Stevens, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A role for septin 2 in Drp1-mediated mitochondrial fission."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "EMBO Rep (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.15252/embr.201541612"}], "href": "https://doi.org/10.15252/embr.201541612"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27215606"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27215606"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Wenbo Yu, Xiangming Ding, Fang Chen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The phosphorylation of SEPT2 on Ser218 by casein kinase 2 is important to hepatoma carcinoma cell proliferation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Biochem (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s11010-008-0020-2"}], "href": "https://doi.org/10.1007/s11010-008-0020-2"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19165576"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19165576"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Liang-Qi Cao, Zi-Li Shao, Hui-Hong Liang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Activation of peroxisome proliferator-activated receptor-γ (PPARγ) inhibits hepatoma cell growth via downregulation of SEPT2 expression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Lett (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.canlet.2015.01.004"}], "href": "https://doi.org/10.1016/j.canlet.2015.01.004"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25592041"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25592041"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Jianhua Yu, Weiguang Zhang, Haijun Tang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Septin 2 accelerates the progression of biliary tract cancer and is negatively regulated by mir-140-5p."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Gene (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.gene.2016.05.005"}], "href": "https://doi.org/10.1016/j.gene.2016.05.005"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27155525"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27155525"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Nianzhu Zhang, Lu Liu, Ning Fan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The requirement of SEPT2 and SEPT7 for migration and invasion in human breast cancer via MEK/ERK activation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncotarget (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.18632/oncotarget.11402"}], "href": "https://doi.org/10.18632/oncotarget.11402"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27557506"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27557506"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Dongchao Xu, Ajuan Liu, Xuan Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Repression of Septin9 and Septin2 suppresses tumor growth of human glioblastoma cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Death Dis (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41419-018-0547-4"}], "href": "https://doi.org/10.1038/s41419-018-0547-4"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29724999"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29724999"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "N Cerveira, C Correia, S Bizarro, et al. "}, {"type": "b", "children": [{"type": "t", "text": "SEPT2 is a new fusion partner of MLL in acute myeloid leukemia with t(2;11)(q37;q23)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/sj.onc.1209626"}], "href": "https://doi.org/10.1038/sj.onc.1209626"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16682951"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16682951"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Takeshi Akama, Tae-Hwa Chun "}, {"type": "b", "children": [{"type": "t", "text": "Transcription factor 21 (TCF21) promotes proinflammatory interleukin 6 expression and extracellular matrix remodeling in visceral adipose stem cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.RA117.000456"}], "href": "https://doi.org/10.1074/jbc.RA117.000456"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29540474"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29540474"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Elizabeth A Marcus, Elmira Tokhtaeva, Shahlo Turdikulova, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Septin oligomerization regulates persistent expression of ErbB2/HER2 in gastric cancer cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem J (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1042/BCJ20160203"}], "href": "https://doi.org/10.1042/BCJ20160203"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27048593"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27048593"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Xiaobo Li, Jinghua Pan, Tongzheng Liu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Novel TCF21"}, {"type": "a", "children": [{"type": "t", "text": "sup"}], "href": "sup"}, {"type": "t", "text": "high"}, {"type": "a", "children": [{"type": "t", "text": "/sup"}], "href": "/sup"}, {"type": "t", "text": " pericyte subpopulation promotes colorectal cancer metastasis by remodelling perivascular matrix."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Gut (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1136/gutjnl-2022-327913"}], "href": "https://doi.org/10.1136/gutjnl-2022-327913"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36805487"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36805487"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Dimitrios Angelis, Eva Pauline Karasmanis, Xiaobo Bai, et al. "}, {"type": "b", "children": [{"type": "t", "text": "In silico docking of forchlorfenuron (FCF) to septins suggests that FCF interferes with GTP binding."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0096390"}], "href": "https://doi.org/10.1371/journal.pone.0096390"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24787956"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24787956"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "Julio Cesar Pissuti Damalio, Wanius Garcia, Joci Neuby Alves Macêdo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Self assembly of human septin 2 into amyloid filaments."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochimie (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.biochi.2011.09.014"}], "href": "https://doi.org/10.1016/j.biochi.2011.09.014"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21967827"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21967827"}]}, {"type": "r", "ref": 22, "children": [{"type": "t", "text": "Venkataramana K Sidhaye, Eric Chau, Patrick N Breysse, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Septin-2 mediates airway epithelial barrier function in physiologic and pathologic conditions."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Respir Cell Mol Biol (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1165/rcmb.2010-0235OC"}], "href": "https://doi.org/10.1165/rcmb.2010-0235OC"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20870893"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20870893"}]}]}]}