The Role of Dimerization of PTPRA in Fibroblast Like Synoviocytes
- Author(s): Lee, Daniel Woei Koung;
- Advisor(s): Bottini, Nunzio;
- et al.
Rheumatoid arthritis is a chronic, progressive autoimmune disease in which fibroblast like synoviocytes (FLS) play a key role. In the pathogenesis of the disease, FLS infiltrate the joints and promote inflammation and destruction of joint cartilage. Tranmembrane protein tyrosine phosphatase receptor type alpha (PTPRA), a known activator of the kinase Src, is highly expressed in RA FLS and promotes their aggressiveness. Knockout of PTPRA protects against joint swelling and disease progression in KBxN models of mice arthritis. A canonical model of transmembrane PTP regulation is that they are inactivated by dimerization. However, these models were never validated by single cell assessments of full length PTPs in primary cells. Here, through FRET microscopy and functional assays of multiple independent primary PTPRA knockout murine FLS cell lines transfected with PTPRA mutant constructs, we show that PTPRA dimerization occurs in FLS and positively correlates with PTPRA association with Src and promotion of cell motility. PTPRA mutants impairing dimerization of PTPRA and its association to Src at the leading edge of migrating mouse FLS also displayed impaired cell morphology and motility. These results are apparently inconsistent with the aforementioned canonical model of transmembrane PTP regulation, indicating the need for further investigations of PTPRA regulation.