{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T17:56:18Z","timestamp":1790618178357,"version":"4.1.0"},"reference-count":57,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T00:00:00Z","timestamp":1790553600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation","doi-asserted-by":"publisher","award":["RS-2021-NR056525"],"award-info":[{"award-number":["RS-2021-NR056525"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation","doi-asserted-by":"publisher","award":["NRF-2015M3A9B5030302"],"award-info":[{"award-number":["NRF-2015M3A9B5030302"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"award":["RS-2021-NR056525"],"award-info":[{"award-number":["RS-2021-NR056525"]}],"id":[{"id":"https:\/\/ror.org\/013aysd81","id-type":"ROR","asserted-by":"publisher"}]},{"award":["NRF-2015M3A9B5030302"],"award-info":[{"award-number":["NRF-2015M3A9B5030302"]}],"id":[{"id":"https:\/\/ror.org\/013aysd81","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Protein tyrosine phosphatase sigma (PTP\u03c3) is a member of the leukocyte common antigen-related (LAR) family of receptor-type protein tyrosine phosphatases. Its architecture integrates an extracellular proteoglycan-sensing region, a single-pass transmembrane helix, and tandem intracellular phosphatase domains. In neural injury, inhibition of PTP\u03c3 signaling can relieve chondroitin sulfate proteoglycan (CSPG)-mediated restriction of axonal growth and plasticity. In rheumatoid arthritis (RA), by contrast, restoration of PTP\u03c3 activity in fibroblast-like synoviocytes can suppress pathogenic migration and invasion. Structural studies have established a proteoglycan-switch model in which glycosaminoglycan engagement of the N-terminal immunoglobulin-like domains and extracellular clustering regulate intracellular phosphatase activity. Recent work demonstrated that antibodies to the membrane-proximal fibronectin type III-like domain 9 (Fn9) can regulate PTP\u03c3 oligomerization and syndecan-4 association in rheumatoid arthritis. Structure-guided protein engineering has converted a poorly soluble PTP\u03c3 Ig1\u2013Ig2 decoy into developable Fc-fusion variants with substantially improved solubility and expression yield while retaining glycosaminoglycan binding and cell-based activity. This review summarizes the structural basis of PTP\u03c3 regulation and evaluates therapeutic modalities and engineering strategies for advancing PTP\u03c3-directed biologics toward clinical candidates.<\/jats:p>","DOI":"10.3390\/ijms27198659","type":"journal-article","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T16:50:54Z","timestamp":1790614254000},"page":"8659","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Structure-Based Engineering for PTP\u03c3-Targeted Therapeutic Development"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-0299-4589","authenticated-orcid":false,"given":"Hyunjin","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Bioengineering, College of Engineering, Hanyang University, Seoul 04673, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3335-326X","authenticated-orcid":false,"given":"Seong Eon","family":"Ryu","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, College of Engineering, Hanyang University, Seoul 04673, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1677\/joe.1.06069","article-title":"Protein tyrosine phosphatases and signalling","volume":"185","author":"Stoker","year":"2005","journal-title":"J. Endocrinol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/S0092-8674(00)81688-8","article-title":"Signaling\u20142000 and beyond","volume":"100","author":"Hunter","year":"2000","journal-title":"Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1016\/j.cell.2008.11.038","article-title":"Large-scale structural analysis of the classical human protein tyrosine phosphatome","volume":"136","author":"Barr","year":"2009","journal-title":"Cell"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1107\/S1399004713029866","article-title":"The family-wide structure and function of human dual-specificity protein phosphatases","volume":"70","author":"Jeong","year":"2014","journal-title":"Acta Crystallogr. Sect. D Biol. Crystallogr."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1038\/nrm2039","article-title":"Protein tyrosine phosphatases: From genes, to function, to disease","volume":"7","author":"Tonks","year":"2006","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1016\/S1367-5931(00)00223-4","article-title":"Protein tyrosine phosphatases: Prospects for therapeutics","volume":"5","author":"Zhang","year":"2001","journal-title":"Curr. Opin. Chem. Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1139\/o04-120","article-title":"Functional significance of the LAR receptor protein tyrosine phosphatase family in development and diseases","volume":"82","author":"Chagnon","year":"2004","journal-title":"Biochem. Cell Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1016\/j.cell.2004.05.018","article-title":"Protein tyrosine phosphatases in the human genome","volume":"117","author":"Alonso","year":"2004","journal-title":"Cell"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1038\/nrc2980","article-title":"Inside the human cancer tyrosine phosphatome","volume":"11","author":"Julien","year":"2011","journal-title":"Nat. Rev. Cancer"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1016\/j.expneurol.2018.01.014","article-title":"Diverse functions of protein tyrosine phosphatase \u03c3 in the nervous and immune systems","volume":"302","author":"Ohtake","year":"2018","journal-title":"Exp. Neurol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1016\/j.tins.2013.06.002","article-title":"Protein tyrosine phosphatases PTP\u03b4, PTP\u03c3, and LAR: Presynaptic hubs for synapse organization","volume":"36","author":"Takahashi","year":"2013","journal-title":"Trends Neurosci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"6722","DOI":"10.1074\/jbc.270.12.6722","article-title":"Molecular characterization of the human transmembrane protein-tyrosine phosphatase delta. Evidence for tissue-specific expression of alternative human transmembrane protein-tyrosine phosphatase delta isoforms","volume":"270","author":"Pulido","year":"1995","journal-title":"J. Biol. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1038\/s41573-022-00618-w","article-title":"Targeting protein phosphatases in cancer immunotherapy and autoimmune disorders","volume":"22","author":"Stanford","year":"2023","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"592","DOI":"10.1126\/science.1178310","article-title":"PTPsigma is a receptor for chondroitin sulfate proteoglycan, an inhibitor of neural regeneration","volume":"326","author":"Shen","year":"2009","journal-title":"Science"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1002\/glia.20934","article-title":"Corticospinal tract regeneration after spinal cord injury in receptor protein tyrosine phosphatase sigma deficient mice","volume":"58","author":"Fry","year":"2010","journal-title":"Glia"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"5481","DOI":"10.1523\/JNEUROSCI.22-13-05481.2002","article-title":"Enhanced rate of nerve regeneration and directional errors after sciatic nerve injury in receptor protein tyrosine phosphatase sigma knock-out mice","volume":"22","author":"McLean","year":"2002","journal-title":"J. Neurosci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1126\/science.1200840","article-title":"Proteoglycan-specific molecular switch for RPTP\u03c3 clustering and neuronal extension","volume":"332","author":"Coles","year":"2011","journal-title":"Science"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1038\/nrn1326","article-title":"Regeneration beyond the glial scar","volume":"5","author":"Silver","year":"2004","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1007\/s12035-012-8346-x","article-title":"Protein tyrosine phosphatase \u03c3 in proteoglycan-mediated neural regeneration regulation","volume":"47","author":"Chien","year":"2013","journal-title":"Mol. Neurobiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1016\/j.neuron.2010.12.024","article-title":"Postsynaptic TrkC and presynaptic PTP\u03c3 function as a bidirectional excitatory synaptic organizing complex","volume":"69","author":"Takahashi","year":"2011","journal-title":"Neuron"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1874","DOI":"10.1073\/pnas.1410138112","article-title":"PTP\u03c3 functions as a presynaptic receptor for the glypican-4\/LRRTM4 complex and is essential for excitatory synaptic transmission","volume":"112","author":"Ko","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1881","DOI":"10.1128\/MCB.22.6.1881-1892.2002","article-title":"Heparan sulfate proteoglycans are ligands for receptor protein tyrosine phosphatase sigma","volume":"22","author":"Aricescu","year":"2002","journal-title":"Mol. Cell. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"5872","DOI":"10.1523\/JNEUROSCI.0386-06.2006","article-title":"Mammalian motoneuron axon targeting requires receptor protein tyrosine phosphatases sigma and delta","volume":"26","author":"Uetani","year":"2006","journal-title":"J. Neurosci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1016\/j.tcb.2013.07.004","article-title":"LAR-RPTPs: Synaptic adhesion molecules that shape synapse development","volume":"23","author":"Um","year":"2013","journal-title":"Trends Cell Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"13966","DOI":"10.1074\/jbc.M109.061127","article-title":"Trans-synaptic adhesions between netrin-G ligand-3 (NGL-3) and receptor tyrosine phosphatases LAR, protein-tyrosine phosphatase delta (PTPdelta), and PTPsigma via specific domains regulate excitatory synapse formation","volume":"285","author":"Kwon","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1002\/jnr.10382","article-title":"Protein tyrosine phosphatase sigma-deficient mice show aberrant cytoarchitecture and structural abnormalities in the central nervous system","volume":"70","author":"Meathrel","year":"2002","journal-title":"J. Neurosci. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1038\/nature13974","article-title":"Modulation of the proteoglycan receptor PTP\u03c3 promotes recovery after spinal cord injury","volume":"518","author":"Lang","year":"2015","journal-title":"Nature"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"6235","DOI":"10.1038\/ncomms7235","article-title":"Targeting protein tyrosine phosphatase \u03c3 after myocardial infarction restores cardiac sympathetic innervation and prevents arrhythmias","volume":"6","author":"Gardner","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1186\/s12974-022-02561-4","article-title":"Modulation of the proteoglycan receptor PTP\u03c3 promotes white matter integrity and functional recovery after intracerebral hemorrhage stroke in mice","volume":"19","author":"Yao","year":"2022","journal-title":"J. Neuroinflamm."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"288ra276","DOI":"10.1126\/scitranslmed.aaa4616","article-title":"Targeting phosphatase-dependent proteoglycan switch for rheumatoid arthritis therapy","volume":"7","author":"Doody","year":"2015","journal-title":"Sci. Transl. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"110470","DOI":"10.1016\/j.jbc.2025.110470","article-title":"Modulation of the PTPRS proteoglycan switch by antibodies binding to the membrane-proximal fibronectin-type III domain","volume":"301","author":"Ramsey","year":"2025","journal-title":"J. Biol. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"5209","DOI":"10.1038\/ncomms6209","article-title":"Structural basis for extracellular cis and trans RPTP\u03c3 signal competition in synaptogenesis","volume":"5","author":"Coles","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Park, S.H., Lim, W., Kang, J., Jo, S., Jang, H.H., Yang, H., Yoo, S.H., Kim, M., and Ryu, S.E. (2025). Structure-Based Engineering of a PTPsigma Ectodomain for Enhanced Solubility and Productivity. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26178345"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"14718","DOI":"10.1038\/s41598-024-65104-2","article-title":"PTPRS is a novel marker for early Tau pathology and synaptic integrity in Alzheimer\u2019s disease","volume":"14","author":"Poirier","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"eaba4353","DOI":"10.1126\/sciadv.aba4353","article-title":"Synoviocyte-targeted therapy synergizes with TNF inhibition in arthritis reversal","volume":"6","author":"Svensson","year":"2020","journal-title":"Sci. Adv."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3667","DOI":"10.1038\/s41467-019-11490-5","article-title":"PTP\u03c3 inhibitors promote hematopoietic stem cell regeneration","volume":"10","author":"Zhang","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1007\/s10059-013-0033-x","article-title":"Structure of the catalytic domain of protein tyrosine phosphatase sigma in the sulfenic acid form","volume":"36","author":"Jeon","year":"2013","journal-title":"Mol. Cells"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1795","DOI":"10.1128\/MCB.00535-06","article-title":"Dimerization of protein tyrosine phosphatase sigma governs both ligand binding and isoform specificity","volume":"27","author":"Lee","year":"2007","journal-title":"Mol. Cell. Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1007\/s10969-007-9036-1","article-title":"Structural genomics of protein phosphatases","volume":"8","author":"Almo","year":"2007","journal-title":"J. Struct. Funct. Genom."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1093\/abbs\/gmr095","article-title":"Structural insights into the homology and differences between mouse protein tyrosine phosphatase-sigma and human protein tyrosine phosphatase-sigma","volume":"43","author":"Hou","year":"2011","journal-title":"Acta Biochim. Biophys. Sin."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1016\/0012-1606(90)90203-U","article-title":"Molecular and cellular characterization of the glial roof plate of the spinal cord and optic tectum: A possible role for a proteoglycan in the development of an axon barrier","volume":"138","author":"Snow","year":"1990","journal-title":"Dev. Biol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1038\/416636a","article-title":"Chondroitinase ABC promotes functional recovery after spinal cord injury","volume":"416","author":"Bradbury","year":"2002","journal-title":"Nature"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/j.conb.2006.09.004","article-title":"The role of extracellular matrix in CNS regeneration","volume":"17","author":"Busch","year":"2007","journal-title":"Curr. Opin. Neurobiol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"14051","DOI":"10.1523\/JNEUROSCI.1737-11.2011","article-title":"Leukocyte common antigen-related phosphatase is a functional receptor for chondroitin sulfate proteoglycan axon growth inhibitors","volume":"31","author":"Fisher","year":"2011","journal-title":"J. Neurosci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1038\/nn.3070","article-title":"NgR1 and NgR3 are receptors for chondroitin sulfate proteoglycans","volume":"15","author":"Dickendesher","year":"2012","journal-title":"Nat. Neurosci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"6289","DOI":"10.1523\/JNEUROSCI.0008-11.2011","article-title":"Integrin activation promotes axon growth on inhibitory chondroitin sulfate proteoglycans by enhancing integrin signaling","volume":"31","author":"Tan","year":"2011","journal-title":"J. Neurosci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/bs.pbr.2015.02.001","article-title":"The extracellular matrix in plasticity and regeneration after CNS injury and neurodegenerative disease","volume":"218","author":"Fawcett","year":"2015","journal-title":"Prog. Brain Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1038\/s41573-020-00135-8","article-title":"Trends in peptide drug discovery","volume":"20","author":"Muttenthaler","year":"2021","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1177","DOI":"10.3390\/ph5111177","article-title":"Improving the endosomal escape of cell-penetrating peptides and their cargos: Strategies and challenges","volume":"5","author":"Muthukrishnan","year":"2012","journal-title":"Pharmaceuticals"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Gessner, I., and Neundorf, I. (2020). Nanoparticles Modified with Cell-Penetrating Peptides: Conjugation Mechanisms, Physicochemical Properties, and Application in Cancer Diagnosis and Therapy. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21072536"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.neuron.2013.10.061","article-title":"Increased brain penetration and potency of a therapeutic antibody using a monovalent molecular shuttle","volume":"81","author":"Niewoehner","year":"2014","journal-title":"Neuron"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1038\/nrrheum.2012.190","article-title":"Duality of fibroblast-like synoviocytes in RA: Passive responders and imprinted aggressors","volume":"9","author":"Bottini","year":"2013","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1111\/j.0105-2896.2009.00859.x","article-title":"Fibroblast-like synoviocytes: Key effector cells in rheumatoid arthritis","volume":"233","author":"Bartok","year":"2010","journal-title":"Immunol. Rev."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1038\/s41584-020-0413-5","article-title":"Restoring synovial homeostasis in rheumatoid arthritis by targeting fibroblast-like synoviocytes","volume":"16","author":"Nygaard","year":"2020","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1038\/s41586-019-1263-7","article-title":"Distinct fibroblast subsets drive inflammation and damage in arthritis","volume":"570","author":"Croft","year":"2019","journal-title":"Nature"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.immuni.2017.02.006","article-title":"Immunopathogenesis of Rheumatoid Arthritis","volume":"46","author":"Firestein","year":"2017","journal-title":"Immunity"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"14923","DOI":"10.1038\/srep14923","article-title":"Enhanced regeneration and functional recovery after spinal root avulsion by manipulation of the proteoglycan receptor PTP\u03c3","volume":"5","author":"Li","year":"2015","journal-title":"Sci. Rep."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/19\/8659\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T17:04:01Z","timestamp":1790615041000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/19\/8659"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,28]]},"references-count":57,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2026,10]]}},"alternative-id":["ijms27198659"],"URL":"https:\/\/doi.org\/10.3390\/ijms27198659","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,28]]}}}