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

doi:10.1038/s41467-017-01168-1

PTP4A1 promotes TGFβ signaling and fibrosis in systemic sclerosis

Nat Commun. 2017 Oct 20;8(1):1060. doi: 10.1038/s41467-017-01168-1.

Authors

Cristiano Sacchetti^{1

2}, Yunpeng Bai³, Stephanie M Stanford^{1

2}, Paola Di Benedetto⁴, Paola Cipriani⁴, Eugenio Santelli^{1

2}, Sonsoles Piera-Velazquez⁵, Vladimir Chernitskiy⁶, William B Kiosses⁷, Arnold Ceponis¹, Klaus H Kaestner⁸, Francesco Boin⁶, Sergio A Jimenez⁵, Roberto Giacomelli⁴, Zhong-Yin Zhang³, Nunzio Bottini^{9

10}

Affiliations

¹ Division of Rheumatology, Allergy and Immunology, Department of Medicine, University of California San Diego, 9500 Gilman Dr, La Jolla, CA, 92093, USA.
² Division of Cellular Biology, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA, 92037, USA.
³ Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 610 Purdue Mall, West Lafayette, IN, 47907, USA.
⁴ Rheumatology Division, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, Via Giovanni di Vincenzo, 16/B, 67100, L'Aquila, Italy.
⁵ Scleroderma Center and Jefferson Institute of Molecular Medicine, 9035 Golden Sunset Ln, Springfield, VA, 22153, USA.
⁶ Division of Rheumatology, Department of Medicine, University of California San Francisco, 505 Parnassus Ave, San Francisco, CA, 94143, USA.
⁷ Core Microscopy Facility, The Scripps Research Institute, 10550 N Torrey Pines Rd, La Jolla, CA, 92037, USA.
⁸ Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
⁹ Division of Rheumatology, Allergy and Immunology, Department of Medicine, University of California San Diego, 9500 Gilman Dr, La Jolla, CA, 92093, USA. nbottini@ucsd.edu.
¹⁰ Division of Cellular Biology, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA, 92037, USA. nbottini@ucsd.edu.

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.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Cell Line
Dermis / pathology
Extracellular Signal-Regulated MAP Kinases / metabolism
Female
Fibroblasts / enzymology
Fibroblasts / metabolism
Humans
Immediate-Early Proteins / antagonists & inhibitors
Immediate-Early Proteins / genetics
Immediate-Early Proteins / metabolism*
Immediate-Early Proteins / physiology
MAP Kinase Signaling System*
Mice, Inbred C57BL
Mice, Knockout
Protein Tyrosine Phosphatases / antagonists & inhibitors
Protein Tyrosine Phosphatases / genetics
Protein Tyrosine Phosphatases / metabolism*
Protein Tyrosine Phosphatases / physiology
Proto-Oncogene Proteins pp60(c-src) / metabolism
Scleroderma, Systemic / enzymology*
Scleroderma, Systemic / metabolism
Scleroderma, Systemic / pathology
Smad3 Protein / metabolism
Transforming Growth Factor beta / physiology*

Substances

Immediate-Early Proteins
SMAD3 protein, human
Smad3 Protein
Transforming Growth Factor beta
Proto-Oncogene Proteins pp60(c-src)
Extracellular Signal-Regulated MAP Kinases
Protein Tyrosine Phosphatases
Ptp4a1 protein, mouse
Ptp4a2 protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding