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, Nunzio Bottini

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16 Scopus citations

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.

Original languageEnglish (US)
Article number1060
JournalNature communications
Volume8
Issue number1
DOIs
StatePublished - Dec 1 2017

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ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Sacchetti, C., Bai, Y., Stanford, S. M., Di Benedetto, P., Cipriani, P., Santelli, E., Piera-Velazquez, S., Chernitskiy, V., Kiosses, W. B., Ceponis, A., Kaestner, K. H., Boin, F., Jimenez, S. A., Giacomelli, R., Zhang, Z. Y., & Bottini, N. (2017). PTP4A1 promotes TGFβ signaling and fibrosis in systemic sclerosis. Nature communications, 8(1), [1060]. https://doi.org/10.1038/s41467-017-01168-1