Inhibition of SHP2 ameliorates psoriasis by decreasing TLR7 endosome localization

Psoriasis is a complex chronic inflammatory skin disease with unclear molecular mechanisms. Here, we identify Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) as a novel accelerator of psoriasis development. Both genetic ablation of SHP2 in macrophages and pharmacological inhibition of SHP2 prevents the development of psoriasis-like skin inflammation in an imiquimod-induced murine model of psoriasis. Mechanistically, SHP2 promotes the trafficking of Toll-like receptor 7 (TLR7) from Golgi to endosome through its interaction with and dephosphorylation of TLR7 at Tyr1024, which promotes the ubiquitination of TLR7 and psoriasis-like skin inflammation. Importantly, SHP2 allosteric inhibitor SHP099 reduces the expression of pro-inflammatory cytokines in peripheral blood mononuclear cells from human patients with psoriasis. Collectively, our findings identify SHP2 as a novel regulator of psoriasis and suggest that SHP2 inhibition may be a promising therapeutic approach for psoriatic patients.

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Differential Localization of Src Homology 2 Domain-Containing Protein Tyrosine Phosphatase Substrate-1 and CD47 and Its Molecular Mechanisms in Cultured Hippocampal Neurons

Journal of Neuroscience ◽

10.1523/jneurosci.5173-04.2005 ◽

2005 ◽

Vol 25 (10) ◽

pp. 2702-2711 ◽

Cited By ~ 29

Author(s):

H. Ohnishi

Keyword(s):

Protein Tyrosine Phosphatase ◽

Hippocampal Neurons ◽

Molecular Mechanisms ◽

Tyrosine Phosphatase ◽

Protein Tyrosine ◽

Src Homology 2 ◽

Src Homology ◽

Src Homology 2 Domain ◽

Phosphatase Substrate ◽

Cultured Hippocampal Neurons

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SHP-2-Induced Activation of c-Myc Is Involved in PDGF-B-Regulated Cell Proliferation and Angiogenesis in RMECs

Frontiers in Physiology ◽

10.3389/fphys.2020.555006 ◽

2020 ◽

Vol 11 ◽

Author(s):

Jun Ma ◽

Wenyi Tang ◽

Ruiping Gu ◽

Fangyuan Hu ◽

Lei Zhang ◽

...

Keyword(s):

Cell Proliferation ◽

Molecular Mechanisms ◽

Tyrosine Phosphatase ◽

Tube Formation ◽

Proliferative Retinopathy ◽

Cell Counting ◽

Brdu Incorporation ◽

Src Homology 2 ◽

Src Homology ◽

Src Homology 2 Domain

Background: Aberrant neovascularization resulting from inappropriate angiogenic signaling is closely related to many diseases, such as cancer, cardiovascular disease, and proliferative retinopathy. Although some factors involved in regulating pathogenic angiogenesis have been identified, the molecular mechanisms of proliferative retinopathy remain largely unknown. In the present study, we determined the role of platelet-derived growth factor-B (PDGF-B), one of the HIF-1-responsive gene products, in cell proliferation and angiogenesis in retinal microvascular endothelial cells (RMECs) and explored its regulatory mechanism.Methods: Cell counting kit-8 (CCK-8), bromodeoxyuridine (BrdU) incorporation, tube formation, cell migration, and Western blot assays were used in our study.Results: Our results showed that PDGF-B promoted cell proliferation and angiogenesis by increasing the activity of Src homology 2 domain-containing tyrosine phosphatase 2 (SHP-2) in RMECs, which was attenuated by the inhibition of PDGF receptor (PDGFR) or SHP-2 knockdown. Moreover, activation of c-Myc was involved in the processes of PDGF-B/SHP-2-driven cell proliferation in RMECs. The promoting effects of PDGF-B/SHP-2 on c-Myc expression were mediated by the Erk pathway.Conclusion: These results indicate that PDGF-B facilitates cell proliferation and angiogenesis, at least in part, via the SHP-2/Erk/c-Myc pathway in RMECs, implying new potential treatment candidates for retinal microangiopathy.

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Investigating the reason for loss-of-function of Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP2) caused by Y279C mutation through molecular dynamics simulation

Journal of Biomolecular Structure and Dynamics ◽

10.1080/07391102.2019.1634641 ◽

2019 ◽

Vol 38 (9) ◽

pp. 2509-2520 ◽

Cited By ~ 2

Author(s):

Wen-Shan Liu ◽

Rui-Rui Wang ◽

Wei-Ya Li ◽

Mei Rong ◽

Chi-Lu Liu ◽

...

Keyword(s):

Molecular Dynamics ◽

Molecular Dynamics Simulation ◽

Protein Tyrosine Phosphatase ◽

Tyrosine Phosphatase ◽

Dynamics Simulation ◽

Loss Of Function ◽

Protein Tyrosine ◽

Src Homology 2 ◽

Src Homology ◽

Src Homology 2 Domain

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Synthesis and biological evaluation of 2,5-diaryl-1,3,4-oxadiazole derivatives as novel Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP2) inhibitors

Bioorganic Chemistry ◽

10.1016/j.bioorg.2021.105384 ◽

2021 ◽

pp. 105384

Author(s):

Xiang-Dong Meng ◽

Li-Xin Gao ◽

Zhi-Jia Wang ◽

Bo Feng ◽

Chun Zhang ◽

...

Keyword(s):

Protein Tyrosine Phosphatase ◽

Tyrosine Phosphatase ◽

Biological Evaluation ◽

Protein Tyrosine ◽

Src Homology 2 ◽

Src Homology ◽

Oxadiazole Derivatives ◽

Src Homology 2 Domain ◽

Synthesis And Biological Evaluation

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Inhibition of Src homology 2 domain containing protein tyrosine phosphatase as the possible mechanism of metformin-assisted amelioration of obesity induced insulin resistance in high fat diet fed C57BL/6J mice

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2017.04.012 ◽

2017 ◽

Vol 487 (1) ◽

pp. 54-61 ◽

Cited By ~ 5

Author(s):

Yadhu Sharma ◽

Samina Bashir ◽

Ansarullah ◽

Mohemmed Faraz Khan ◽

Altaf Ahmad ◽

...

Keyword(s):

Insulin Resistance ◽

Protein Tyrosine Phosphatase ◽

High Fat Diet ◽

Tyrosine Phosphatase ◽

High Fat ◽

Protein Tyrosine ◽

Src Homology 2 ◽

Src Homology ◽

Src Homology 2 Domain

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Design, synthesis, biological evaluation, common feature pharmacophore model and molecular dynamics simulation studies of ethyl 4-(phenoxymethyl)-2-phenylthiazole-5-carboxylate as Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) inhibitors

Journal of Biomolecular Structure and Dynamics ◽

10.1080/07391102.2020.1726817 ◽

2020 ◽

pp. 1-15 ◽

Cited By ~ 3

Author(s):

Jingwei Wu ◽

Weiya Li ◽

Zhihui Zheng ◽

Xinhua Lu ◽

Huan Zhang ◽

...

Keyword(s):

Protein Tyrosine Phosphatase ◽

Tyrosine Phosphatase ◽

Pharmacophore Model ◽

Biological Evaluation ◽

Dynamics Simulation ◽

Simulation Studies ◽

Design Synthesis ◽

Src Homology 2 ◽

Src Homology ◽

Src Homology 2 Domain

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Chicken Ig-Like Receptor B2, a Member of a Multigene Family, Is Mainly Expressed on B Lymphocytes, Recruits Both Src Homology 2 Domain Containing Protein Tyrosine Phosphatase (SHP)-1 and SHP-2, and Inhibits Proliferation

The Journal of Immunology ◽

10.4049/jimmunol.173.12.7385 ◽

2004 ◽

Vol 173 (12) ◽

pp. 7385-7393 ◽

Cited By ~ 29

Author(s):

Birgit C. Viertlboeck ◽

Richard P. M. A. Crooijmans ◽

Martien A. M. Groenen ◽

Thomas W. F. Göbel

Keyword(s):

B Lymphocytes ◽

Protein Tyrosine Phosphatase ◽

Multigene Family ◽

Tyrosine Phosphatase ◽

Protein Tyrosine ◽

Src Homology 2 ◽

Src Homology ◽

Src Homology 2 Domain

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Leishmania EF-1α Activates the Src Homology 2 Domain Containing Tyrosine Phosphatase SHP-1 Leading to Macrophage Deactivation

Journal of Biological Chemistry ◽

10.1074/jbc.m209210200 ◽

2002 ◽

Vol 277 (51) ◽

pp. 50190-50197 ◽

Cited By ~ 98

Author(s):

Devki Nandan ◽

Taolin Yi ◽

Martin Lopez ◽

Crystal Lai ◽

Neil E. Reiner

Keyword(s):

Leishmania Donovani ◽

Tyrosine Phosphatase ◽

Elongation Factor ◽

Host Protein ◽

Src Homology 2 ◽

Infected Cells ◽

Src Homology ◽

Src Homology 2 Domain

The human leishmaniasis are persistent infections of macrophages caused by protozoa of the genusLeishmania.The chronic nature of these infections is in part related to induction of macrophage deactivation, linked to activation of the Src homology 2 domain containing tyrosine phosphatase-1 (SHP-1) in infected cells. To investigate the mechanism of SHP-1 activation, lysates ofLeishmania donovanipromastigotes were subjected to SHP-1 affinity chromatography and proteins bound to the matrix were sequenced by mass spectrometry. This resulted in the identification ofLeishmaniaelongation factor-1α (EF-1α) as a SHP-1-binding protein. PurifiedLeishmaniaEF-1α, but not host cell EF-1α, bound directly to SHP-1in vitroleading to its activation. Three independent lines of evidence indicated thatLeishmaniaEF-1α may be exported from the phagosome thereby enabling targeting of host SHP-1. First, cytosolic fractions prepared from macrophages infected with [35S]methionine-labeled organisms containedLeishmaniaEF-1α. Second, confocal, fluorescence microscopy usingLeishmania-specific antisera detectedLeishmaniaEF-1α in the cytosol of infected cells. Third, co-immunoprecipitation showed thatLeishmaniaEF-1α was associated with SHP-1in vivoin infected cells. Finally, introduction of purifiedLeishmaniaEF-1α, but not the corresponding host protein into macrophages activated SHP-1 and blocked the induction of inducible nitric-oxide synthase expression in response to interferon-γ. Thus,LeishmaniaEF-1α is identified as a novel SHP-1-binding and activating protein that recapitulates the deactivated phenotype of infected macrophages.

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