PTP4A1 promotes TGFβ signaling and fibrosis in systemic sclerosis

• Published in: Nature communications 2017-10, Vol.8 (1), p.1060-14, Article 1060
• Main Authors: Sacchetti, Cristiano, Bai, Yunpeng, Stanford, Stephanie M., Di Benedetto, Paola, Cipriani, Paola, Santelli, Eugenio, Piera-Velazquez, Sonsoles, Chernitskiy, Vladimir, Kiosses, William B., Ceponis, Arnold, Kaestner, Klaus H., Boin, Francesco, Jimenez, Sergio A., Giacomelli, Roberto, Zhang, Zhong-Yin, Bottini, Nunzio
• Format: Article
• Language: English
• Subjects: 631/250/127/1219; 692/699/1670/122/1801; Animals; Bleomycin; Cell Line; Dermis - pathology; Extracellular Signal-Regulated MAP Kinases - metabolism; Female; Fibroblasts; Fibroblasts - enzymology; Fibroblasts - metabolism; Fibrosis; Homology; Humanities and Social Sciences; Humans; Immediate-Early Proteins - antagonists & inhibitors; Immediate-Early Proteins - genetics; Immediate-Early Proteins - metabolism; Immediate-Early Proteins - physiology; Kinases; MAP Kinase Signaling System; Mice, Inbred C57BL; Mice, Knockout; multidisciplinary; Nuclear transport; Organs; Patients; Phosphatase; Promoters; Protein Tyrosine Phosphatases - antagonists & inhibitors; Protein Tyrosine Phosphatases - genetics; Protein Tyrosine Phosphatases - metabolism; Protein Tyrosine Phosphatases - physiology; Protein-tyrosine-phosphatase; Proteins; Proto-Oncogene Proteins pp60(c-src) - metabolism; Science; Science (multidisciplinary); Scleroderma; Scleroderma, Systemic - enzymology; Scleroderma, Systemic - metabolism; Scleroderma, Systemic - pathology; Signaling; Smad3 protein; Smad3 Protein - metabolism; Src protein; Systemic sclerosis; Transforming Growth Factor beta - physiology; Translocation; Tyrosine
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-017-01168-1

Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of skin and internal organs. Protein tyrosine phosphatases have received little attention in the study of SSc or fibrosis. Here, we show that the tyrosine phosphatase PTP4A1 is highly expressed in fibroblasts from patients with SSc. PTP4A1 and its close homolog PTP4A2 are critical promoters of TGFβ signaling in primary dermal fibroblasts and of bleomycin-induced fibrosis in vivo. PTP4A1 promotes TGFβ signaling in human fibroblasts through enhancement of ERK activity, which stimulates SMAD3 expression and nuclear translocation. Upstream from ERK, we show that PTP4A1 directly interacts with SRC and inhibits SRC basal activation independently of its phosphatase activity. Unexpectedly, PTP4A2 minimally interacts with SRC and does not promote the SRC–ERK–SMAD3 pathway. Thus, in addition to defining PTP4A1 as a molecule of interest for TGFβ-dependent fibrosis, our study provides information regarding the functional specificity of different members of the PTP4A subclass of phosphatases. Although protein tyrosine kinases are being explored as antifibrotic agents for the treatment of systemic sclerosis, little is known about the function of counteractive protein tyrosine phosphatases in this context. Here, the authors show that PTP4A1 is highly expressed by fibroblasts from patients with systemic sclerosis and promotes TGFβ activity via SRC–ERK–SMAD3 signaling.