Protein tyrosine phosphatases ε and α perform nonredundant roles in osteoclasts

Finkelshtein, Eynat; Lotinun, Sutada; Levy-Apter, Einat; Arman, Esther; Hertog, Jeroen den; Baron, Roland; Elson, Ari

doi:10.1091/mbc.e14-03-0788

Cited by 15 publications

(10 citation statements)

References 57 publications

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“…RPTPα‐KO mice displayed significantly decreased arthritis severity, as assessed by measurements of ankle swelling (Figure A), joint inflammation (using an intravital probe) (Figure B), and bone and cartilage erosions (Figure C). RPTPα‐KO does not cause a bone phenotype per se , suggesting that RPTPα promotes K/BxN serum–induced bone erosion through an effect on inflammation.…”

Section: Resultsmentioning

confidence: 98%

Receptor Protein Tyrosine Phosphatase α–Mediated Enhancement of Rheumatoid Synovial Fibroblast Signaling and Promotion of Arthritis in Mice

Stanford

Svensson

Sacchetti

et al. 2016

Arthritis & Rheumatology

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Objective During rheumatoid arthritis (RA), fibroblast-like synoviocytes (FLS) critically promote disease pathogenesis by aggressively invading the joint extracellular matrix. The focal adhesion kinase (FAK) signaling pathway is emerging as a contributor to RA FLS anomalous behavior. The receptor protein tyrosine phosphatase α (RPTPα), encoded by the PTPRA gene, is a key promoter of FAK signaling. Here we investigated whether RPTPα mediates FLS aggressiveness and RA pathogenesis. Methods Through RPTPα knockdown, we assessed FLS gene expression by quantitative polymerase chain reaction and enzyme-linked immunosorbent assay, invasion and migration in transwell assays, survival by Annexin V and propidium iodide staining, adhesion and spreading by immunofluorescence microscopy, and activation of signaling pathways by Western blotting of FLS lysates. Arthritis development was examined in Ptpra−/− mice using the K/BxN serum transfer model. The contribution of radiosensitive and radioresistant cells to disease was evaluated by reciprocal bone-marrow transplantation. Results RPTPα was enriched in the RA synovial lining. RPTPα knockdown impaired RA FLS survival, spreading, migration, invasiveness and responsiveness to platelet-derived growth factor, tumor necrosis factor and interleukin-1 stimulation. These phenotypes correlated with increased phosphorylation of SRC on inhibitory Y527 and decreased phosphorylation of FAK on stimulatory Y397. Treatment of RA FLS with an inhibitor of FAK phenocopied knockdown of RPTPα. Ptpra-deficient mice were protected from arthritis development, which was due to radioresistant cells. Conclusions By regulating phosphorylation of SRC and FAK, RPTPα mediates pro-inflammatory and pro-invasive signaling in RA FLS, correlating with promotion of disease in an FLS-dependent model of RA.

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Section: Resultsmentioning

confidence: 98%

Receptor Protein Tyrosine Phosphatase α–Mediated Enhancement of Rheumatoid Synovial Fibroblast Signaling and Promotion of Arthritis in Mice

Stanford

Svensson

Sacchetti

et al. 2016

Arthritis & Rheumatology

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“…Cyt-PTP« is involved in inhibiting JAK/STAT signaling by dephosphorylation of STAT1 and STAT3 in murine M1 cells (Tanuma et al, 2000(Tanuma et al, , 2001(Tanuma et al, , 2003. Also, osteoclast function is influenced by the presence of cyt-PTP« as the phosphatase allows a functional rearrangement of podosomes through Src activation (Chiusaroli et al, 2004;Granot-Attas et al, 2009;Finkelshtein et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Role of Protein Tyrosine Phosphatase Epsilon (PTPε) in Leukotriene D₄-Induced CXCL8 Expression

Lapointe

Turcotte

Véronneau

et al. 2019

J Pharmacol Exp Ther

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Phosphorylation on tyrosine residues is recognized as an important mechanism for connecting extracellular stimuli to cellular events and defines a variety of physiologic responses downstream of G protein-coupled receptor (GPCR) activation. To date, few protein tyrosine phosphatases (PTPs) have been shown to associate with GPCRs, and little is known about their role in GPCR signaling. To discover potential cysteinyl-leukotriene receptor (CysLT 1 R)-interacting proteins, we identified protein tyrosine phosphatase « (PTP«) in a yeast two-hybrid assay. Since both proteins are closely linked to asthma, we further investigated their association. Using a human embryonic kidney cell line 293 (HEK-293) cell line stably transfected with the receptor (HEK-LT1), as well as human primary monocytes, we found that PTP« colocalized with CysLT 1 R in both resting and leukotriene D4 (LTD 4 )stimulated cells. Cotransfection of HEK-LT1 with PTP« had no effect on CysLT 1 R expression or LTD 4 -induced internalization, but it inhibited LTD 4 -induced CXC chemokine 8 (CXCL8) promoter transactivation, protein expression, and secretion. Moreover, reduced phosphorylation of extracellular signal regulated kinase 1/2 (ERK1/2), but not of p38 or c-Jun-Nterminal kinase 1 or 2 mitogen-activated protein kinases (MAPKs), was observed upon LTD 4 stimulation of HEK-LT1 coexpressing cytosolic (cyt-) PTP«, but not receptor (R) PTP«. The increased interaction of cyt-PTP« and ERK1/2 after LTD 4 stimulation was shown by coimmunoprecipitation. In addition, enhanced ERK1/2 phosphorylation and CXCL8 secretion were found in LTD 4 -stimulated human monocytes transfected with PTP«-specific siRNAs, adding support to a regulatory/inhibitory role of PTP« in CysLT 1 R signaling. Given that the prevalence of severe asthma is increasing, the identification of PTP« as a new potential therapeutic target may be of interest.

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“…5C). a sealing zone-like structure characteristic of mature, active OCLs (9,30). Because reduced expression of GRB2 inhibited activation of Src by cyt-PTPe (Fig.…”

Section: Grb2 Promotes Phosphorylation Of Cyt-ptpe and Activation Of mentioning

confidence: 95%

“…On day 2 or 3 of differentiation, cells were infected with adenoviruses or lentiviruses as described above. After 4 days of differentiation, OCLs were fixed in paraformaldehyde and stained with phalloidin to visualize actin as described (30). Images were collected with an inverted microscope (Olympus Corp., Tokyo, Japan).…”

Section: Analysis Of Podosomal Organization In Oclsmentioning

confidence: 99%

Adaptor Protein GRB2 Promotes Src Tyrosine Kinase Activation and Podosomal Organization by Protein-tyrosine Phosphatase ϵ in Osteoclasts

Levy-Apter

Finkelshtein

Vemulapalli

et al. 2014

Journal of Biological Chemistry

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Background: Protein-tyrosine phosphatase ⑀ (cyt-PTPe) dephosphorylates and activates Src to promote osteoclast adhesion. Results: The adaptor protein GRB2 binds phosphorylated cyt-PTPe and recruits Src, thus promoting its activation. Conclusion: GRB2 links cyt-PTPe to Src downstream of activated integrins in osteoclasts.Significance: GRB2-mediated recruitment may constitute a general mechanism by which cyt-PTPe activates Src and related kinases.

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Protein tyrosine phosphatases ε and α perform nonredundant roles in osteoclasts

Cited by 15 publications

References 57 publications

Receptor Protein Tyrosine Phosphatase α–Mediated Enhancement of Rheumatoid Synovial Fibroblast Signaling and Promotion of Arthritis in Mice

Receptor Protein Tyrosine Phosphatase α–Mediated Enhancement of Rheumatoid Synovial Fibroblast Signaling and Promotion of Arthritis in Mice

Role of Protein Tyrosine Phosphatase Epsilon (PTPε) in Leukotriene D₄-Induced CXCL8 Expression

Adaptor Protein GRB2 Promotes Src Tyrosine Kinase Activation and Podosomal Organization by Protein-tyrosine Phosphatase ϵ in Osteoclasts

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Protein tyrosine phosphatases ε and α perform nonredundant roles in osteoclasts

Cited by 15 publications

References 57 publications

Receptor Protein Tyrosine Phosphatase α–Mediated Enhancement of Rheumatoid Synovial Fibroblast Signaling and Promotion of Arthritis in Mice

Receptor Protein Tyrosine Phosphatase α–Mediated Enhancement of Rheumatoid Synovial Fibroblast Signaling and Promotion of Arthritis in Mice

Role of Protein Tyrosine Phosphatase Epsilon (PTPε) in Leukotriene D4-Induced CXCL8 Expression

Adaptor Protein GRB2 Promotes Src Tyrosine Kinase Activation and Podosomal Organization by Protein-tyrosine Phosphatase ϵ in Osteoclasts

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Role of Protein Tyrosine Phosphatase Epsilon (PTPε) in Leukotriene D₄-Induced CXCL8 Expression