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PTP4A1 promotes TGFβ signaling and fibrosis in systemic sclerosis

Cristiano Sacchetti1,2, Yunpeng Bai3, Stephanie M Stanford1,2

  • 1Division of Rheumatology, Allergy and Immunology, Department of Medicine, University of California San Diego, 9500 Gilman Dr, La Jolla, CA, 92093, USA.

Nature Communications
|October 24, 2017
PubMed

Insights

Systemic sclerosis (SSc) involves fibrosis. This study identifies tyrosine phosphatase PTP4A1 as highly expressed in SSc fibroblasts, promoting fibrosis by enhancing TGFβ signaling via the ERK pathway.

Area of Science:

  • Biochemistry
  • Immunology
  • Cell Biology

Background:

  • Systemic sclerosis (SSc) is an autoimmune disease causing fibrosis.
  • Protein tyrosine phosphatases (PTPs) are understudied in SSc and fibrosis.
  • PTP4A1 and PTP4A2 are homologs within the PTP4A subclass of phosphatases.

Purpose of the Study:

  • Investigate the role of PTP4A1 in SSc and fibrosis.
  • Elucidate the mechanism by which PTP4A1 influences TGFβ signaling.
  • Determine the functional specificity of PTP4A1 and PTP4A2 in fibrosis.

Main Methods:

  • Analysis of PTP4A1 expression in SSc patient fibroblasts.
  • Assessment of PTP4A1 and PTP4A2 roles in TGFβ signaling in vitro.
  • Evaluation of bleomycin-induced fibrosis models in vivo.
  • Investigation of molecular interactions using techniques like co-immunoprecipitation.

Main Results:

  • PTP4A1 is highly expressed in SSc fibroblasts.
  • PTP4A1 promotes TGFβ signaling and fibrosis in vivo.
  • PTP4A1 enhances ERK activity, leading to SMAD3 expression and nuclear translocation.
  • PTP4A1 interacts with SRC, inhibiting its basal activity, independent of phosphatase function.
  • PTP4A2 shows minimal SRC interaction and does not promote the SRC-ERK-SMAD3 pathway.

Conclusions:

  • PTP4A1 is a key promoter of TGFβ-dependent fibrosis in SSc.
  • PTP4A1's mechanism involves regulating the SRC-ERK-SMAD3 pathway.
  • PTP4A1 represents a potential therapeutic target for SSc.
  • Functional specificity exists within the PTP4A phosphatase subclass.

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