Protein Tyrosine Phosphatases in Systemic Sclerosis: Potential Pathogenic Players and Therapeutic Targets

Abstract

Purpose of review: The pathogenesis of systemic sclerosis depends on a complex interplay between autoimmunity, vasculopathy, and fibrosis. Reversible phosphorylation on tyrosine residues, in response to growth factors and other stimuli, critically regulates each one of these three key pathogenic processes. Protein tyrosine kinases, the enzymes that catalyze addition of phosphate to tyrosine residues, are known players in systemic sclerosis, and tyrosine kinase inhibitors are undergoing clinical trials for treatment of this disease. Until recently, the role of tyrosine phosphatases-the enzymes that counteract the action of tyrosine kinases by removing phosphate from tyrosine residues-in systemic sclerosis has remained largely unknown. Here, we review the function of tyrosine phosphatases in pathways relevant to the pathogenesis of systemic sclerosis and their potential promise as therapeutic targets to halt progression of this debilitating rheumatic disease.

Recent findings: Protein tyrosine phosphatases are emerging as important regulators of a multitude of signaling pathways and undergoing validation as molecular targets for cancer and other common diseases. Recent advances in drug discovery are paving the ways to develop new classes of tyrosine phosphatase modulators to treat human diseases. Although so far only few reports have focused on tyrosine phosphatases in systemic sclerosis, these enzymes play a role in multiple pathways relevant to disease pathogenesis. Further studies in this field are warranted to explore the potential of tyrosine phosphatases as drug targets for systemic sclerosis.

Keywords: Molecular target; Protein tyrosine phosphatase; Protein tyrosine phosphorylation; Signal transduction; Systemic sclerosis.

Figure 1.

The SSc pathogenic triad occurs through the interconnection between inflammation and autoimmunity, vascular injury and fibrosis. The major metabolic pathways in SSc pathogenesis are represented clustered around the triad components. Red arrows show inflammation and autoimmunity influence, and include the interleukin receptors 4 (IL-4R), 6 (IL-6R), 13 (IL-13R), toll-like receptor 4 (TLR4) and Fc gamma receptor (FcgR) signaling pathways. Blue arrows show vascular injury affecting SSc, including vascular endothelial growth factor receptor (VEGFR), prostacyclin receptor (PTGIR) and endothelin receptor (ETa-b) signaling pathway. Green arrows show fibrotic effects such as transforming growth factor beta (TGFβ), platelet-derived growth factor receptors (PDGFR), connective tissue growth factor (CTGF) and lysophosphatidic acid receptor 1 (LPAR1) signaling pathways. PTPs affecting those pathways are showed with a ↓ or ↑ arrow to indicate the inhibitory or enhancing effect.

Figure 2.

PTP activity can be controlled allosterically using small-molecules to bind PTP-specific pockets, which in turn generate a conformational modification in the catalytic site.