PTP4A1 promotes TGFβ signaling and fibrosis in systemic sclerosis

• DOI: 10.1038/s41467-017-01168-1
• Publication Date: 2017-10-16T14:57:18Z
• Authors: Cristiano Sacchetti; Yunpeng Bai; Stephanie M. Stan...; Paola Di Benedetto; Paola Cipriani; Eugenio Santelli; Sonsoles Piera-Ve...; Vladimir Chernitskiy; William B. Kiosses; Arnold Ceponis; Klaus H. Kaestner; Francesco Boin; Sergio A. Jimenez; Roberto Giacomelli; Zhong-Yin Zhang; Nunzio Bottini
• Keywords: 572; MAP Kinase Signaling System; Knockout; Science; Proto-Oncogene Proteins pp60(c-src); Inbred C57BL; Autoimmune Disease; Article; Scleroderma; Cell Line; Immediate-Early Proteins; Mice; 03 medical and health sciences; Rare Diseases; Clinical Research; Transforming Growth Factor beta; Animals; Humans; Smad3 Protein; Extracellular Signal-Regulated MAP Kinases; Mice, Knockout; 0303 health sciences; Scleroderma, Systemic; Systemic; Q; Dermis; Fibroblasts; 3. Good health; Mice, Inbred C57BL; Female; Protein Tyrosine Phosphatases

AbstractSystemic 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.