PTP4A1 promotes TGFβ signaling and fibrosis in systemic sclerosis

Cristiano Sacchetti, Yunpeng Bai, Stephanie M. Stanford, Paola Di Benedetto, Paola Cipriani, Eugenio Santelli, Sonsoles Piera-Velazquez, Vladimir Chernitskiy, William B. Kiosses, Arnold Ceponis, Klaus H. Kaestner, Francesco Boin, Sergio A. Jimenez, Roberto Giacomelli, Zhong-Yin Zhang and Nunzio Bottini ()
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Cristiano Sacchetti: University of California San Diego
Yunpeng Bai: Purdue University
Stephanie M. Stanford: University of California San Diego
Paola Di Benedetto: University of L’Aquila
Paola Cipriani: University of L’Aquila
Eugenio Santelli: University of California San Diego
Sonsoles Piera-Velazquez: Scleroderma Center and Jefferson Institute of Molecular Medicine
Vladimir Chernitskiy: University of California San Francisco
William B. Kiosses: The Scripps Research Institute
Arnold Ceponis: University of California San Diego
Klaus H. Kaestner: University of Pennsylvania
Francesco Boin: University of California San Francisco
Sergio A. Jimenez: Scleroderma Center and Jefferson Institute of Molecular Medicine
Roberto Giacomelli: University of L’Aquila
Zhong-Yin Zhang: Purdue University
Nunzio Bottini: University of California San Diego

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: Abstract 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.

Date: 2017
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DOI: 10.1038/s41467-017-01168-1

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