{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPTPN23 (also known as HD‐PTP) plays a central role in endosomal protein trafficking by serving as an adaptor that links ubiquitinated cargo to the endosomal sorting complexes required for transport (ESCRT). In this capacity, PTPN23 regulates the delivery of ubiquitinated receptors – including the epidermal growth factor receptor and MHC class I – into intralumenal vesicles for lysosomal degradation. Structural studies have revealed that its coiled‐coil (“V”) domain interacts specifically with ESCRT‐I components such as UBAP1 and with the ATPase Vps4, thereby facilitating ESCRT‐III–driven membrane scission. Moreover, regulation of PTPN23 levels by ubiquitin ligases further modulates receptor trafficking and downstream signaling."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its role in endosomal sorting, PTPN23 functions as a haploinsufficient tumor suppressor in multiple cellular contexts. Loss or suppression of PTPN23 leads to aberrant activation of oncogenic kinases such as SRC and FYN, enhanced phosphorylation of key adhesion proteins (for example, the E‐cadherin/β‑catenin complex) and focal adhesion kinase, and consequent increases in cell motility, invasion, and tumorigenesis. In diverse tumor models – from breast and testicular cancers to bladder carcinoma – depletion or mutation of PTPN23 correlates with disrupted receptor turnover and aggressive cell behavior."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "11"}, {"type": "fg_f", "ref": "5"}, {"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nPTPN23 also influences cell migration and adhesion through its regulation of the cytoskeleton and integrin trafficking. In endothelial and epithelial cells, its interaction with key kinases such as SRC and focal adhesion kinase—as well as its control over integrin recycling—modulates the dynamics of cell–cell contacts and focal adhesions. These actions are critical for controlling endothelial motility during angiogenesis and for maintaining epithelial integrity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "13", "end_ref": "19"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition, PTPN23 has emerging roles in modulating the phosphorylation state of proteins that govern RNA splicing and neurodevelopment. Although its intrinsic phosphatase activity has been subject to debate, PTPN23 has been implicated in maintaining a hyperphosphorylated state of the survival motor neuron (SMN) complex, which is essential for proper snRNP assembly. Furthermore, rare biallelic mutations in PTPN23 are now associated with severe neurodevelopmental phenotypes—including developmental and epileptic encephalopathies—underscoring its importance in nervous system function."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "20", "end_ref": "24"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Nazim Ali, Ling Zhang, Sandra Taylor, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Recruitment of UBPY and ESCRT exchange drive HD-PTP-dependent sorting of EGFR to the MVB."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Curr Biol (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cub.2013.02.033"}], "href": "https://doi.org/10.1016/j.cub.2013.02.033"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23477725"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23477725"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Michael D J Parkinson, Siân C Piper, Nicholas A Bright, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A non-canonical ESCRT pathway, including histidine domain phosphotyrosine phosphatase (HD-PTP), is used for down-regulation of virally ubiquitinated MHC class I."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem J (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1042/BJ20150336"}], "href": "https://doi.org/10.1042/BJ20150336"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26221024"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26221024"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Sanaz Manteghi, Marie-Claude Gingras, Dmitri Kharitidi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Haploinsufficiency of the ESCRT Component HD-PTP Predisposes to Cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Rep (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.celrep.2016.04.076"}], "href": "https://doi.org/10.1016/j.celrep.2016.04.076"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27210750"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27210750"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Deepankar Gahloth, Colin Levy, Graham Heaven, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structural Basis for Selective Interaction between the ESCRT Regulator HD-PTP and UBAP1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Structure (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.str.2016.10.006"}], "href": "https://doi.org/10.1016/j.str.2016.10.006"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27839950"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27839950"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Marie-Claude Gingras, Jalal M Kazan, Arnim Pause "}, {"type": "b", "children": [{"type": "t", "text": "Role of ESCRT component HD-PTP/"}, {"type": "a", "children": [{"type": "t", "text": "i"}], "href": "i"}, {"type": "t", "text": "PTPN23"}, {"type": "a", "children": [{"type": "t", "text": "/i"}], "href": "/i"}, {"type": "t", "text": " in cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Soc Trans (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1042/BST20160332"}], "href": "https://doi.org/10.1042/BST20160332"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28620046"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28620046"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Siwei Zhang, Gaofeng Fan, Yuan Hao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Suppression of protein tyrosine phosphatase N23 predisposes to breast tumorigenesis via activation of FYN kinase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genes Dev (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1101/gad.304261.117"}], "href": "https://doi.org/10.1101/gad.304261.117"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29066500"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29066500"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Natalya Pashkova, Liping Yu, Nicholas J Schnicker, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Interactions of ubiquitin and CHMP5 with the V domain of HD-PTP reveals role for regulation of Vps4 ATPase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Biol Cell (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1091/mbc.E21-04-0219"}], "href": "https://doi.org/10.1091/mbc.E21-04-0219"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34586919"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34586919"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Shaifali Singh, Nai Yang Yeat, Ya-Ting Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PTPN23 ubiquitination by WDR4 suppresses EGFR and c-MET degradation to define a lung cancer therapeutic target."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Death Dis (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41419-023-06201-4"}], "href": "https://doi.org/10.1038/s41419-023-06201-4"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "37821451"}], "href": "https://pubmed.ncbi.nlm.nih.gov/37821451"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Massimo Mariotti, Sara Castiglioni, Jeanette A M Maier "}, {"type": "b", "children": [{"type": "t", "text": "Inhibition of T24 human bladder carcinoma cell migration by RNA interference suppressing the expression of HD-PTP."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Lett (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.canlet.2008.08.017"}], "href": "https://doi.org/10.1016/j.canlet.2008.08.017"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18835089"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18835089"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Guang Lin, Victoria Aranda, Senthil K Muthuswamy, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Identification of PTPN23 as a novel regulator of cell invasion in mammary epithelial cells from a loss-of-function screen of the 'PTP-ome'."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genes Dev (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1101/gad.2018911"}], "href": "https://doi.org/10.1101/gad.2018911"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21724833"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21724833"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Kiyoko Tanaka, Keiichi Kondo, Kenji Kitajima, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Tumor-suppressive function of protein-tyrosine phosphatase non-receptor type 23 in testicular germ cell tumors is lost upon overexpression of miR142-3p microRNA."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M113.478891"}], "href": "https://doi.org/10.1074/jbc.M113.478891"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23843459"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23843459"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Siyuan Niu, Jialing Ma, Yueping Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PTPN23[Thr] variant reduces susceptibility and tumorigenesis in esophageal squamous cell carcinoma through dephosphorylation of EGFR."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Lett (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.canlet.2024.216936"}], "href": "https://doi.org/10.1016/j.canlet.2024.216936"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38704135"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38704135"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Massimo Mariotti, Sara Castiglioni, Jeanette A M Maier "}, {"type": "b", "children": [{"type": "t", "text": "Expression analysis and modulation by HIV-Tat of the tyrosine phosphatase HD-PTP."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Biochem (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/jcb.20770"}], "href": "https://doi.org/10.1002/jcb.20770"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16408268"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16408268"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Massimo Mariotti, Sara Castiglioni, Laura Beguinot, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The tyrosine phosphatase HD-PTP is regulated by FGF-2 through proteasome degradation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Front Biosci (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.2741/1956"}], "href": "https://doi.org/10.2741/1956"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16720300"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16720300"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Sara Castiglioni, Jeanette A M Maier, Massimo Mariotti "}, {"type": "b", "children": [{"type": "t", "text": "The tyrosine phosphatase HD-PTP: A novel player in endothelial migration."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2007.10.022"}], "href": "https://doi.org/10.1016/j.bbrc.2007.10.022"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17959146"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17959146"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Massimo Mariotti, Sara Castiglioni, Jose M Garcia-Manteiga, et al. "}, {"type": "b", "children": [{"type": "t", "text": "HD-PTP inhibits endothelial migration through its interaction with Src."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Biochem Cell Biol (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.biocel.2008.08.005"}], "href": "https://doi.org/10.1016/j.biocel.2008.08.005"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18762272"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18762272"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Carmen-Alexandra Tanase "}, {"type": "b", "children": [{"type": "t", "text": "Histidine domain-protein tyrosine phosphatase interacts with Grb2 and GrpL."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0014339"}], "href": "https://doi.org/10.1371/journal.pone.0014339"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21179510"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21179510"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Sara Castiglioni, Jeanette A M Maier "}, {"type": "b", "children": [{"type": "t", "text": "The tyrosine phosphatase HD-PTP (PTPN23) is degraded by calpains in a calcium-dependent manner."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2012.04.024"}], "href": "https://doi.org/10.1016/j.bbrc.2012.04.024"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22510412"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22510412"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Dong-Yuan Chen, Meng-Yen Li, Shih-Yun Wu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The Bro1-domain-containing protein Myopic/HDPTP coordinates with Rab4 to regulate cell adhesion and migration."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Sci (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1242/jcs.108597"}], "href": "https://doi.org/10.1242/jcs.108597"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22825871"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22825871"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Marie-Claude Gingras, Yu Ling Zhang, Dmitri Kharitidi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "HD-PTP is a catalytically inactive tyrosine phosphatase due to a conserved divergence in its phosphatase domain."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0005105"}], "href": "https://doi.org/10.1371/journal.pone.0005105"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19340315"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19340315"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "Alma Husedzinovic, Beate Neumann, Jürgen Reymann, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The catalytically inactive tyrosine phosphatase HD-PTP/PTPN23 is a novel regulator of SMN complex localization."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Biol Cell (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1091/mbc.E14-06-1151"}], "href": "https://doi.org/10.1091/mbc.E14-06-1151"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25392300"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25392300"}]}, {"type": "r", "ref": 22, "children": [{"type": "t", "text": "Nadine Sowada, Mais Omar Hashem, Rüstem Yilmaz, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mutations of PTPN23 in developmental and epileptic encephalopathy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Genet (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00439-017-1850-3"}], "href": "https://doi.org/10.1007/s00439-017-1850-3"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29090338"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29090338"}]}, {"type": "r", "ref": 23, "children": [{"type": "t", "text": "Robert Smigiel, Gerd Landsberg, Maximilian Schilling, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Developmental epileptic encephalopathy with hypomyelination and brain atrophy associated with PTPN23 variants affecting the assembly of UsnRNPs."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Hum Genet (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41431-018-0179-2"}], "href": "https://doi.org/10.1038/s41431-018-0179-2"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29899372"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29899372"}]}, {"type": "r", "ref": 24, "children": [{"type": "t", "text": "Renee Bend, Lior Cohen, Melissa T Carter, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Phenotype and mutation expansion of the PTPN23 associated disorder characterized by neurodevelopmental delay and structural brain abnormalities."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Hum Genet (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41431-019-0487-1"}], "href": "https://doi.org/10.1038/s41431-019-0487-1"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31395947"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31395947"}]}]}]}