학술논문
Clustering of phosphatase RPTPα promotes Src signaling and the arthritogenic action of synovial fibroblasts.
Document Type
Academic Journal
Author
Sendo S; Department of Medicine, University of California San Diego, La Jolla, CA, USA.; Kiosses WB; Department of Medicine, University of California San Diego, La Jolla, CA, USA.; La Jolla Institute for Immunology, La Jolla, CA, USA.; Yang S; Department of Medicine, University of California San Diego, La Jolla, CA, USA.; Wu DJ; Department of Medicine, University of California San Diego, La Jolla, CA, USA.; Lee DWK; Department of Medicine, University of California San Diego, La Jolla, CA, USA.; Liu L; Department of Medicine, University of California San Diego, La Jolla, CA, USA.; Aschner Y; Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado, Aurora, CO, USA.; Vela AJ; Department of Medicine, University of California San Diego, La Jolla, CA, USA.; Downey GP; Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, National Jewish Health, Denver, CO, USA.; Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado, Aurora, CO, USA.; Department of Biomedical Research, National Jewish Health, Denver, CO, USA.; Department of Immunology and Microbiology, University of Colorado, Aurora, CO, USA.; Department of Pediatrics, National Jewish Health, Denver, CO, USA.; Santelli E; Department of Medicine, University of California San Diego, La Jolla, CA, USA.; Bottini N; Department of Medicine, University of California San Diego, La Jolla, CA, USA.; Department of Medicine, Kao Autoimmunity Institute, Cedars Sinai Medical Center, Los Angeles, CA, USA.
Source
Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 101465400 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1937-9145 (Electronic) Linking ISSN: 19450877 NLM ISO Abbreviation: Sci Signal Subsets: MEDLINE
Subject
Language
English
Abstract
Receptor-type protein phosphatase α (RPTPα) 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. RPTPα 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 RPTPα dimerization in the activation of SRC, the migration of synovial fibroblasts, and joint damage in a mouse model of arthritis. RPTPα clustered with other RPTPα 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 RPTPα-RPTPα clustering; however, it also unexpectedly reduced RPTPα-SRC association. The same mutations also reduced recruitment of RPTPα to actin-rich structures and inhibited SRC activation and cellular migration. An antibody against the RPTPα ectodomain that prevented the clustering of RPTPα also inhibited RPTPα-SRC association and SRC activation and attenuated fibroblast migration and joint damage in arthritic mice. A catalytically inactivating RPTPα-C469S mutation protected mice from arthritis and reduced SRC activation in synovial fibroblasts. We conclude that RPTPα clustering retains it to actin-rich structures to promote SRC-mediated fibroblast migration and can be modulated through the extracellular domain.