Non-Receptor Protein Tyrosine Phosphatase 14 (PTPN14) Promotes YAP-Dependent Tgfbeta Signaling in RA FLS

Angel Bottini¹, Dennis J. Wu², Rizi Ai³, Michelle LeRoux⁴, Beatrix Bartok¹, Michele Bombardieri⁵, Vida Zhang⁶, Karen M. Doody⁷, Cristiano Sacchetti¹, Martina Zoccheddu¹, Ana Lonic⁸, David L. Boyle⁹, Deepa Hammaker⁹, Tzu-Ching Meng¹⁰, Maripat Corr³, Stephanie M. Stanford³, Myles J. Lewis¹¹, Wei Wang¹², Gary S. Firestein⁹, Yeesim Khew-Goodall⁸, Costantino Pitzalis¹³ and Nunzio Bottini¹⁴, ¹Rheumatology, University of California San Diego, La Jolla, CA, ²University of California San Diego, San Diego, CA, ³University of California San Diego, La Jolla, CA, ⁴La Jolla Institute for Allergy and Immunology, LA JOLLA, CA, ⁵Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Queen Mary University of London, London, United Kindgdom, London, United Kingdom, ⁶La Jolla Institute for Allergy and Immunology, La Jolla, CA, ⁷Cellular Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA, ⁸SA Pathology and University of South Australia, Adelaide, Australia, ⁹Medicine, University of California San Diego, La Jolla, CA, ¹⁰Academia Sinica, Taipei, Taiwan, ¹¹Barts Health NHS Trust & Barts and the London School of Medicine & Dentistry, London, United Kingdom, London, United Kingdom, ¹²Chemistry and Biochemistry, University of California San Diego, La Jolla, CA, ¹³Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom, ¹⁴Medicine/Rheumatology, University of California San Diego, La Jolla, CA

Meeting: 2018 ACR/ARHP Annual Meeting

Keywords: Rheumatoid arthritis (RA)

Session Information

Date: Monday, October 22, 2018

Session Title: Rheumatoid Arthritis – Etiology and Pathogenesis Poster II

Session Type: ACR Poster Session B

Session Time: 9:00AM-11:00AM

Background/Purpose:

Non-Receptor Protein Tyrosine Phosphatase 14 (PTPN14) was identified in a phosphatase expression profile survey to be highly expressed in synovial fibroblasts derived from patients with rheumatoid arthritis (RA FLS). PTPN14 is a negative regulator of transcriptional co-activator YAP -a key Hippo pathway player- in cancer cells. Here we aimed to investigate the role of PTPN14 in RA FLS.

Methods:

Gene expression level in RA FLS and FLS from osteoarthritis patients (OA FLS) was measured by qPCR. Specific gene knockdown was achieved using antisense oligonucleotides. PTPN14, YAP and SMAD3 protein expression levels were visualized in Western blotting and immunofluorescence. Immunoprecipitation was used to detect protein-protein interaction. The passive K/BxN arthritis and RA FLS/cartilage co-implantation models were used to assess effects of chemical inhibition of YAP.

Results:

RA FLS displayed TGFbeta-dependent overexpression of PTPN14 compared to OA FLS (p < 0.01). PTPN14 knockdown in RA FLS impaired TGFbeta-dependent expression of matrix metalloproteinase 13 (p < 0.05) and potentiation of inflammatory cytokine signaling. In RA FLS, PTPN14 forms a complex with YAP, promoting TGFbeta-dependent YAP and SMAD3 nuclear localizations. Chemical inhibition of YAP inhibited RA FLS pathogenic behavior and ameliorated arthritis severity in vivo (p < 0.0001).

Conclusion:

In RA FLS, TGFbeta-dependent PTPN14 overexpression acts as a positive feedback TGFbeta-signaling regulator. Surprisingly, in RA FLS PTPN14 enhances nuclear YAP-mediated promotion of SMAD signaling. YAP promotes a wide range of RA FLS pathogenic behaviors, pointing to the Hippo pathway as a potential important regulator of RA FLS and a player in RA pathogenesis.

Disclosure: A. Bottini, None; D. J. Wu, None; R. Ai, None; M. LeRoux, None; B. Bartok, None; M. Bombardieri, None; V. Zhang, None; K. M. Doody, None; C. Sacchetti, None; M. Zoccheddu, None; A. Lonic, None; D. L. Boyle, None; D. Hammaker, None; T. C. Meng, None; M. Corr, None; S. M. Stanford, None; M. J. Lewis, None; W. Wang, None; G. S. Firestein, None; Y. Khew-Goodall, None; C. Pitzalis, None; N. Bottini, Roche, 2,Eli Lilly and Co., 2,Kyowa Kirin Pharmaceutical Research, Inc., 2.

To cite this abstract in AMA style:

Bottini A, Wu DJ, Ai R, LeRoux M, Bartok B, Bombardieri M, Zhang V, Doody KM, Sacchetti C, Zoccheddu M, Lonic A, Boyle DL, Hammaker D, Meng TC, Corr M, Stanford SM, Lewis MJ, Wang W, Firestein GS, Khew-Goodall Y, Pitzalis C, Bottini N. Non-Receptor Protein Tyrosine Phosphatase 14 (PTPN14) Promotes YAP-Dependent Tgfbeta Signaling in RA FLS [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10). https://acrabstracts.org/abstract/non-receptor-protein-tyrosine-phosphatase-14-ptpn14-promotes-yap-dependent-tgfbeta-signaling-in-ra-fls/. Accessed July 2, 2020.

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