Protein Tyrosine Phosphatase Expression Profile of Rheumatoid Arthritis Fibroblast‐like Synoviocytes: A Novel Role of SH2 Domain–Containing Phosphatase 2 as a Modulator of Invasion and Survival

The fibroblast-like synoviocytes (FLS) present in the intimal lining of the synovium are primary pathogenic effectors in rheumatoid arthritis (RA) (1–5). In healthy individuals, these mesenchymal-derived cells provide structural and dynamic support for diarthrodial joints and secrete components of synovial fluid. In RA however, FLS become aggressive and invasive, displaying some characteristics of transformed cells. RA FLS are resistant to apoptosis, and contribute to the inflammatory milieu by producing pro-inflammatory cytokines. They also secrete matrix metalloproteinases (MMPs) that break down the extracellular matrix and cartilage, participate in the bone-eroding pannus formation, and promote angiogenesis to the joint. Direct targeting of FLS in RA is increasingly being considered as an option for new therapies aimed at ameliorating the course of disease. A complex network of intracellular signaling pathways controls the behavior of RA FLS (1, 3). Many of these pathways involve reversible phosphorylation of proteins on tyrosine residues (1). Tyrosine phosphorylation results from the balanced action of protein tyrosine kinases (PTKs) and phosphatases (PTPs) (6). The involvement of PTKs in FLS growth and invasiveness is currently under investigation. For example, several receptors for key pathogenic growth factors in RA, such as Fibroblast Growth Factor (FGF) and Platelet-Derived Growth Factor (PDGF), are active PTKs (7, 8). On the other hand, with the exception of the phosphoinositol-specific Phosphatase and Tensin Homolog (PTEN) and the dual-specificity (phosphoserine/phosphothreonine and phosphotyrosine) MAP Kinase Phosphatase 1 (MKP-1) (9, 10), the vast majority of PTPs controlling FLS intracellular signaling–including all of the tyrosine-specific enzymes – remains unexplored. The human genome contains more than 100 PTPs (termed the PTPome (11)), which are divided into 4 classes (6). The Class I PTP subfamily includes most of the tyrosine-specific PTPs and several subfamilies of dual-specificity PTPs (DSPs). The Class II family contains a single gene, ACP1, encoding the low molecular weight PTP. The Class III family contains the Cell Division Cycle 25 (CDC25) subfamily of cell cycle regulators. The Class IV family contains the EYA genes, encoding the Eyes Absent PTPs, which employ a unique catalytic mechanism. Two novel PTPs have also been recently identified: Suppressor of SUa7, gene 2 (SSU72) (6, 12) and Ubiquitin-associated and SH3-domain containing A (UBASH3A) (13). Here, we profiled the PTPome in human FLS. After first performing an expression survey in RA FLS, we next identified that PTPN11 is overexpressed in RA FLS compared to FLS from osteoarthritis (OA) patients. Further functional studies were performed on this gene, which encodes the SH2-domain Containing PTP 2 (SHP-2), a known proto-oncogene and drug target for cancer (14, 15). Consistent with its role as a very upstream promoter of growth factor and cytokine signaling (16), we found that SHP-2 promotes both survival and invasion of RA FLS. We propose a novel role for SHP-2 in mediating the aggressive phenotype of FLS in RA.