{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPPFIA1, which encodes liprin‐α1, plays a critical role in the organization and function of synapses. In neurons, liprin‐α1 participates in presynaptic active zone assembly by directly interacting with ERC/CAST proteins and orchestrating the clustering of essential release machinery. Its levels are dynamically regulated by synaptic activity and Ca²⁺/calmodulin‐dependent protein kinase II–mediated degradation, a process important for proper dendritic arborization and receptor targeting. In addition, liprin‐α1 self‐assembles via conserved coiled‐coil domains and engages in phosphorylation‐dependent interactions with LAR receptor phosphatases, thereby contributing to synaptic protein compartmentalization and even modulating Hedgehog signaling through ciliary trafficking."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nOutside the nervous system, liprin‐α1 is a pivotal regulator of cell adhesion and motility. It modulates the dynamics of integrin receptors at the plasma membrane by stabilizing inactive β1 integrins, thus influencing lamellipodia formation and focal adhesion turnover. Through its involvement in the recycling of active integrins and the basolateral secretion and polymerization of fibronectin, liprin‐α1 directs endothelial cell polarity and vascular morphogenesis. In tumor cells, these functions translate into the control of protrusive activity, invadopodia formation, and extracellular matrix remodeling, underscoring its role in regulated cell–matrix interactions that orchestrate both normal cell migration and pathological invasion."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "17"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn disease contexts, aberrant expression or genomic amplification of PPFIA1 has been documented in various cancers—including head and neck, breast, and esophageal carcinomas—where its dysregulation correlates with altered cell–matrix interactions and oncogenic signaling (for example, via the RAS/MAPK cascade). In some tumors, PPFIA1 overexpression appears to restrain invasive behavior, while in others it facilitates migration and metastasis, especially in estrogen receptor–positive, nodal‐negative breast cancer. Moreover, increased liprin‐α1 expression has been observed in neurological disorders such as intractable epilepsy, signifying its broad impact across tissues. Together, these findings highlight liprin‐α1 as a multifunctional scaffold protein whose control of synapse assembly, integrin dynamics, and signaling compartmentalization is critical for normal development as well as for the progression of diverse pathological conditions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "18", "end_ref": "24"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Jaewon Ko, Moonseok Na, Seho Kim, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Interaction of the ERC family of RIM-binding proteins with the liprin-alpha family of multidomain proteins."}]}, {"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.M307561200"}], "href": "https://doi.org/10.1074/jbc.M307561200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12923177"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12923177"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Carles Serra-Pagès, Michel Streuli, Quintus G Medley "}, {"type": "b", "children": [{"type": "t", "text": "Liprin phosphorylation regulates binding to LAR: evidence for liprin autophosphorylation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochemistry (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1021/bi051434f"}], "href": "https://doi.org/10.1021/bi051434f"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16313174"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16313174"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Casper C Hoogenraad, Monica I Feliu-Mojer, Samantha A Spangler, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Liprinalpha1 degradation by calcium/calmodulin-dependent protein kinase II regulates LAR receptor tyrosine phosphatase distribution and dendrite development."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Dev Cell (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.devcel.2007.02.006"}], "href": "https://doi.org/10.1016/j.devcel.2007.02.006"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17419996"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17419996"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Hidenori Taru, Yishi Jin "}, {"type": "b", "children": [{"type": "t", "text": "The Liprin homology domain is essential for the homomeric interaction of SYD-2/Liprin-α protein in presynaptic assembly."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neurosci (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1523/JNEUROSCI.0002-11.2011"}], "href": "https://doi.org/10.1523/JNEUROSCI.0002-11.2011"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22072677"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22072677"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Yulu C Liu, Amber L Couzens, Ashish R Deshwar, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The PPFIA1-PP2A protein complex promotes trafficking of Kif7 to the ciliary tip and Hedgehog signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Signal (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1126/scisignal.2005608"}], "href": "https://doi.org/10.1126/scisignal.2005608"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25492966"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25492966"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Mingfu Liang, Gaowei Jin, Xingqiao Xie, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Oligomerized liprin-α promotes phase separation of ELKS for compartmentalization of presynaptic active zone proteins."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Rep (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.celrep.2021.108901"}], "href": "https://doi.org/10.1016/j.celrep.2021.108901"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33761347"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33761347"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Claudia Asperti, Veronica Astro, Antonio Totaro, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Liprin-alpha1 promotes cell spreading on the extracellular matrix by affecting the distribution of activated integrins."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Sci (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1242/jcs.054155"}], "href": "https://doi.org/10.1242/jcs.054155"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19690048"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19690048"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Claudia Asperti, Emanuela Pettinato, Ivan de Curtis "}, {"type": "b", "children": [{"type": "t", "text": "Liprin-alpha1 affects the distribution of low-affinity beta1 integrins and stabilizes their permanence at the cell surface."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Exp Cell Res (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.yexcr.2010.01.017"}], "href": "https://doi.org/10.1016/j.yexcr.2010.01.017"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20096687"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20096687"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Jason D Christie, Mark M Wurfel, Rui Feng, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genome wide association identifies PPFIA1 as a candidate gene for acute lung injury risk following major trauma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0028268"}], "href": "https://doi.org/10.1371/journal.pone.0028268"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22295056"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22295056"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Veronica Astro, Sara Chiaretti, Elisa Magistrati, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Liprin-α1, ERC1 and LL5 define polarized and dynamic structures that are implicated in cell migration."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Sci (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1242/jcs.155663"}], "href": "https://doi.org/10.1242/jcs.155663"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24982445"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24982445"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Sara Chiaretti, Veronica Astro, Elena Chiricozzi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Effects of the scaffold proteins liprin-α1, β1 and β2 on invasion by breast cancer cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biol Cell (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/boc.201500063"}], "href": "https://doi.org/10.1111/boc.201500063"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26663347"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26663347"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Henna Pehkonen, Pernilla von Nandelstadh, Piia-Riitta Karhemo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Liprin-α1 is a regulator of vimentin intermediate filament network in the cancer cell adhesion machinery."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Rep (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/srep24486"}], "href": "https://doi.org/10.1038/srep24486"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27075696"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27075696"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Giulia Mana, Fabiana Clapero, Emiliano Panieri, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PPFIA1 drives active α5β1 integrin recycling and controls fibronectin fibrillogenesis and vascular morphogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Commun (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ncomms13546"}], "href": "https://doi.org/10.1038/ncomms13546"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27876801"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27876801"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Henna Pehkonen, Mira Lento, Pernilla von Nandelstadh, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Liprin-α1 modulates cancer cell signaling by transmembrane protein CD82 in adhesive membrane domains linked to cytoskeleton."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Commun Signal (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/s12964-018-0253-y"}], "href": "https://doi.org/10.1186/s12964-018-0253-y"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30005669"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30005669"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Hong Zhou, Ting Cao, Wen Ping Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Combined expression and prognostic significance of PPFIA1 and ALG3 in head and neck squamous cell carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Biol Rep (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s11033-019-04712-y"}], "href": "https://doi.org/10.1007/s11033-019-04712-y"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30805892"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30805892"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Yongyin Gao, Lizhao Guan, Ran Jia, et al. "}, {"type": "b", "children": [{"type": "t", "text": "High expression of PPFIA1 in human esophageal squamous cell carcinoma correlates with tumor metastasis and poor prognosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "BMC Cancer (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/s12885-023-10872-9"}], "href": "https://doi.org/10.1186/s12885-023-10872-9"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "37158817"}], "href": "https://pubmed.ncbi.nlm.nih.gov/37158817"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Henna Pehkonen, Artemis Filippou, Juho Väänänen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Liprin-α1 contributes to oncogenic MAPK signaling by counteracting ERK activity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Oncol (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/1878-0261.13593"}], "href": "https://doi.org/10.1002/1878-0261.13593"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38264964"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38264964"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Kaia Davis Tan, Yansong Zhu, Hiang Khoon Tan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Amplification and overexpression of PPFIA1, a putative 11q13 invasion suppressor gene, in head and neck squamous cell carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genes Chromosomes Cancer (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/gcc.20539"}], "href": "https://doi.org/10.1002/gcc.20539"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18196592"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18196592"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Ana-Maria Dancau, Laura Wuth, Marcel Waschow, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PPFIA1 and CCND1 are frequently coamplified in breast cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genes Chromosomes Cancer (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/gcc.20713"}], "href": "https://doi.org/10.1002/gcc.20713"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19787783"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19787783"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Huan Yin, Linyuan Wang, Fei Xiao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Upregulation of liprin-α1 protein in the temporal neocortex of intractable epileptic patients and experimental rats."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Synapse (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/syn.20894"}], "href": "https://doi.org/10.1002/syn.20894"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21157931"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21157931"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "Marco Blessmann, Ahmed Al-Dam, Henning Hanken, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Amplification of the PPFIA1 gene region on 11q13 in oral squamous cell carcinomas (OSCC)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Craniomaxillofac Surg (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jcms.2013.01.040"}], "href": "https://doi.org/10.1016/j.jcms.2013.01.040"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23453270"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23453270"}]}, {"type": "r", "ref": 22, "children": [{"type": "t", "text": "Jing Yang, Ning-Ni Wu, De-Jia Huang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PPFIA1 is upregulated in liver metastasis of breast cancer and is a potential poor prognostic indicator of metastatic relapse."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Tumour Biol (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1177/1010428317713492"}], "href": "https://doi.org/10.1177/1010428317713492"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28720060"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28720060"}]}, {"type": "r", "ref": 23, "children": [{"type": "t", "text": "Kristyna Sala, Andrea Raimondi, Diletta Tonoli, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Identification of a membrane-less compartment regulating invadosome function and motility."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Rep (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41598-018-19447-2"}], "href": "https://doi.org/10.1038/s41598-018-19447-2"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29348417"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29348417"}]}, {"type": "r", "ref": 24, "children": [{"type": "t", "text": "Fabiana Clapero, Dora Tortarolo, Donatella Valdembri, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Quantifying Polarized Extracellular Matrix Secretion in Cultured Endothelial Cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Methods Mol Biol (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/978-1-0716-0962-0_17"}], "href": "https://doi.org/10.1007/978-1-0716-0962-0_17"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33215388"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33215388"}]}]}]}