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PTP4A1 promotes TGFβ signaling and fibrosis in systemic sclerosis.

Nature communications | Oct 20, 2017

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.

Pubmed ID: 29057934 RIS Download

Mesh terms: Animals | Cell Line | Dermis | Extracellular Signal-Regulated MAP Kinases | Female | Fibroblasts | Humans | Immediate-Early Proteins | MAP Kinase Signaling System | Mice, Inbred C57BL | Mice, Knockout | Protein Tyrosine Phosphatases | Proto-Oncogene Proteins pp60(c-src) | Scleroderma, Systemic | Smad3 Protein | Transforming Growth Factor beta

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