{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T11:45:58Z","timestamp":1790768758121,"version":"4.1.0"},"reference-count":82,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"792","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Signal."],"published-print":{"date-parts":[[2023,7,4]]},"abstract":"<jats:p>Receptor-type protein phosphatase \u03b1 (RPTP\u03b1) promotes fibroblast-dependent arthritis and fibrosis, in part, by enhancing the activation of the kinase SRC. Synovial fibroblasts lining joint tissue mediate inflammation and tissue damage, and their infiltration into adjacent tissues promotes disease progression. RPTP\u03b1 includes an ectodomain and two intracellular catalytic domains (D1 and D2) and, in cancer cells, undergoes inhibitory homodimerization, which is dependent on a D1 wedge motif. Through single-molecule localization and labeled molecule interaction microscopy of migrating synovial fibroblasts, we investigated the role of RPTP\u03b1 dimerization in the activation of SRC, the migration of synovial fibroblasts, and joint damage in a mouse model of arthritis. RPTP\u03b1 clustered with other RPTP\u03b1 and with SRC molecules in the context of actin-rich structures. A known dimerization-impairing mutation in the wedge motif (P210L\/P211L) and the deletion of the D2 domain reduced RPTP\u03b1-RPTP\u03b1 clustering; however, it also unexpectedly reduced RPTP\u03b1-SRC association. The same mutations also reduced recruitment of RPTP\u03b1 to actin-rich structures and inhibited SRC activation and cellular migration. An antibody against the RPTP\u03b1 ectodomain that prevented the clustering of RPTP\u03b1 also inhibited RPTP\u03b1-SRC association and SRC activation and attenuated fibroblast migration and joint damage in arthritic mice. A catalytically inactivating RPTP\u03b1-C469S mutation protected mice from arthritis and reduced SRC activation in synovial fibroblasts. We conclude that RPTP\u03b1 clustering retains it to actin-rich structures to promote SRC-mediated fibroblast migration and can be modulated through the extracellular domain.<\/jats:p>","DOI":"10.1126\/scisignal.abn8668","type":"journal-article","created":{"date-parts":[[2023,7,4]],"date-time":"2023-07-04T18:01:14Z","timestamp":1688493674000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":6,"title":["Clustering of phosphatase RPTP\u03b1 promotes Src signaling and the arthritogenic action of synovial fibroblasts"],"prefix":"10.1126","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7193-341X","authenticated-orcid":true,"given":"Sho","family":"Sendo","sequence":"first","affiliation":[{"name":"Department of Medicine, University of California San Diego, La Jolla, CA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1832-9050","authenticated-orcid":true,"given":"William B.","family":"Kiosses","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of California San Diego, La Jolla, CA, USA."},{"name":"La Jolla Institute for Immunology, La Jolla, CA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4983-6787","authenticated-orcid":true,"given":"Shen","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of California San Diego, La Jolla, CA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6021-5607","authenticated-orcid":true,"given":"Dennis J.","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of California San Diego, La Jolla, CA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-1974-2294","authenticated-orcid":true,"given":"Daniel W. 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