NSC-87877, inhibitor of SHP-1/2 PTPs, inhibits dual-specificity phosphatase 26 (DUSP26)

Song, Minseok; Park, Jae Eun; Park, Sung Goo; Lee, Do Hee; Choi, Hyung‐Kyoon; Park, Byoung Chul; Ryu, Seong Eon; Kim, Jae-Hoon; Cho, Sayeon

doi:10.1016/j.bbrc.2009.02.069

Cited by 58 publications

(39 citation statements)

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“…The physiological relevance of these findings was shown with in vitro endothelial tube formation and migration assays, in which we demonstrated using both pharmacologic and genetic approaches that inhibition of VEGF signaling by TSR was mediated by CD36 and SHP-1. Although the SHP inhibitor blocks both SHP-1 and SHP-2 activity, 33,34 our data show that the association of SHP-2 was not affected by VEGF or TSR, and that SHP-2 did not contribute to TSR-induced VEGFR2 dephosphorylation or inhibition of migration in MVEC. Our work demonstrates, in vitro and in vivo, that CD36, SHP-1, and VEGFR2 are components of a liganddependent, detergent-sensitive, multiprotein complex.…”

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confidence: 73%

Thrombospondin-1 modulates VEGF signaling via CD36 by recruiting SHP-1 to VEGFR2 complex in microvascular endothelial cells

Chu

Ramakrishnan

Silverstein

2013

Blood

133

110

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• TSP-1 binding to CD36 recruits SHP-1 to CD36-VEGFR2 complex in microvascular endothelial cells.• SHP-1 recruitment to CD36-VEGFR2 complex dephosphorylates VEGFR2 and inhibits angiogenesis.Thrombospondin-1 (TSP-1) inhibits growth factor signaling at the receptor level in microvascular endothelial cells (MVEC), and CD36 has been suggested to be involved in this inhibition, but the mechanisms are not known. We hypothesized that CD36-TSP-1 interaction recruits Src homology 2 domain-containing protein tyrosine phosphatase (SHP)-1 to the vascular endothelial growth factor receptor 2 (VEGFR2) signaling complex and attenuates vascular endothelial growth factor (VEGF) signaling. Western blots of anti-CD36 and anti-VEGFR2 immunoprecipitates from VEGF-treated MVEC showed that exposure of the cells to a recombinant protein containing the CD36 binding domain of thrombospondin-1 (known as the TSR domain) induced association of SHP-1 with the VEGFR2/CD36 signaling complex and thereby suppressed VEGFR2 phosphorylation. SHP-1 phosphatase activity was increased in immunoprecipitated VEGFR2 complexes from TSR-treated cells. Silencing CD36 expression in MVEC by small interfering RNA (siRNA) or genetic deletion of cd36 in mice showed that TSR-induced SHP-1/VEGFR2 complex formation required CD36 in vitro and in vivo. Silencing SHP-1 expression in MVEC by siRNA abrogated TSR-mediated inhibition of VEGFR2 phosphorylation as well as TSRmediated inhibition of VEGF-induced endothelial cell migration and tube formation. These studies reveal a SHP-1-mediated antiangiogenic pathway induced by CD36-TSP-1 interaction that inhibits VEGFR2 signaling and they provide a novel target to modulate angiogenesis therapeutically. (Blood. 2013;122(10):1822-1832 Introduction CD36 is a multiligand scavenger receptor expressed on the surface of platelets, MVEC, mononuclear phagocytes, adipocytes, hepatocytes, myocytes, and some epithelia.1 It was first identified as glycoprotein IV on platelets.2 On MVEC, CD36 is a receptor for TSP-1 and related proteins containing the so-called "thrombospondin type I structural homology domain (TSR)." It functions as a negative regulator of angiogenesis 1,[3][4][5] and therefore plays a role in tumor growth, inflammation, wound healing, and other pathological processes requiring neovascularization. 6,7 Binding of TSP-1 or TSR proteins to CD36 inhibits growth factor-induced proangiogenic signals that mediate endothelial cell proliferation, migration, and tube formation, and instead generates antiangiogenic signals that lead to apoptosis. 4,8 In vivo, CD36 null mice exhibit an increase in vessel density in the brain, an organ in which early angiogenesis is modulated by high levels of TSP-1, increased tumor angiogenesis in subcutaneously injected TSP-expressing tumor cells, and a lack of response to antiangiogenic effect of TSP-1 in in vivo angiogenesis assays. 8,9 It was recently shown that TSP-1 also inhibits growth factor signaling at the vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) receptor level in end...

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confidence: 73%

Thrombospondin-1 modulates VEGF signaling via CD36 by recruiting SHP-1 to VEGFR2 complex in microvascular endothelial cells

Chu

Ramakrishnan

Silverstein

2013

Blood

133

110

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“…Because PD1 receptor signaling occurs via SHP1/2(20, 30), we hypothesized that ex vivo pharmacologic inhibition of this pathway using pervanadate(20) or NSC87877(31, 32) might generate Th1 cells (Th1.SHP1/2 in ) resistant to the tolerizing effect of PDL1. SHP1/2 inhibition did not influence Th1 cell engraftment (Fig.…”

Section: Resultsmentioning

confidence: 99%

The PDL1-PD1 Axis Converts Human T _H 1 Cells into Regulatory T Cells

et al. 2011

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Immune surveillance by T helper type 1 (Th1) cells is critical for the host response to tumors and infection, but also contributes to autoimmunity and graft-versus-host disease (GvHD) after transplantation. The inhibitory molecule programmed death ligand-1 (PDL1) has been shown to anergize human Th1 cells, but other mechanisms of PDL1-mediated Th1 inhibition such as the conversion of Th1 cells to a regulatory phenotype have not been well characterized. We hypothesized that PDL1 may cause Th1 cells to manifest differentiation plasticity. Conventional T cells or irradiated K562 myeloid tumor cells overexpressing PDL1 converted TBET+ Th1 cells into FOXP3+ regulatory T cells (TREGS) in vivo, thereby preventing human-into-mouse xenogeneic GvHD (xGvHD). Either blocking PD1 expression on Th1 cells by siRNA targeting or abrogation of PD1 signaling by SHP1/2 pharmacologic inhibition stabilized Th1 cell differentiation during PDL1 challenge and restored the capacity of Th1 cells to mediate lethal xGVHD. PD1 signaling therefore induces human Th1 cells to manifest in vivo plasticity, resulting in a TREG phenotype that severely impairs cell-mediated immunity. Converting human Th1 cells to a regulatory phenotype with PD1 signaling provides a potential way to block GvHD after transplantation. Moreover, because this conversion can be prevented by blocking PD1 expression or pharmacologically inhibiting SHP1/2, this pathway provides a new therapeutic direction for enhancing T cell immunity to cancer and infection.

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“…Notably, ERK1/2 dephosphorylation was attenuated by SHP-1 inhibitor. Furthermore, SHP-1 dephosphorylates vascular endothelial growth factor (VEGF)-induced ERK phosphorylation in endothelial cells [35]. In contrast to iITAM, SIRP-1a, ITIM-bearing receptor, inhibits lipopolysaccharide/TLR-4-mediated signalling primarily through sequestering SHP-2 but not SHP-1 [36], suggesting that different inhibitory receptors may utilize divergent intracellular phosphatases to elicit their inhibitory effects.…”

Section: Discussionmentioning

confidence: 99%

Negative regulation of inflammatory responses by immunoglobulin A receptor (FcαRI) inhibits the development of Toll-like receptor-9 signalling-accelerated glomerulonephritis

Watanabe

Kanamaru

Liu

et al. 2011

Clinical and Experimental Immunology

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SummaryMyeloid FcaRI, a receptor for immunoglobulin (Ig)A, mediates cell activation or inhibition depending on the type of ligand interaction, which can be either multivalent or monovalent. Anti-inflammatory signalling is triggered by monomeric targeting using anti-FcaRI Fab or IgA ligand binding, which inhibits immune and non-immune-mediated renal inflammation. The participation of Toll-like receptors (TLRs) in kidney pathology in experimental models and various forms of human glomerular nephritis has been discussed. However, little is known about negative regulation of innate-immune activation. In the present study, we generated new transgenic mice that express

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NSC-87877, inhibitor of SHP-1/2 PTPs, inhibits dual-specificity phosphatase 26 (DUSP26)

Cited by 58 publications

References 14 publications

Thrombospondin-1 modulates VEGF signaling via CD36 by recruiting SHP-1 to VEGFR2 complex in microvascular endothelial cells

Thrombospondin-1 modulates VEGF signaling via CD36 by recruiting SHP-1 to VEGFR2 complex in microvascular endothelial cells

The PDL1-PD1 Axis Converts Human T _H 1 Cells into Regulatory T Cells

Negative regulation of inflammatory responses by immunoglobulin A receptor (FcαRI) inhibits the development of Toll-like receptor-9 signalling-accelerated glomerulonephritis

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NSC-87877, inhibitor of SHP-1/2 PTPs, inhibits dual-specificity phosphatase 26 (DUSP26)

Cited by 58 publications

References 14 publications

Thrombospondin-1 modulates VEGF signaling via CD36 by recruiting SHP-1 to VEGFR2 complex in microvascular endothelial cells

Thrombospondin-1 modulates VEGF signaling via CD36 by recruiting SHP-1 to VEGFR2 complex in microvascular endothelial cells

The PDL1-PD1 Axis Converts Human T H 1 Cells into Regulatory T Cells

Negative regulation of inflammatory responses by immunoglobulin A receptor (FcαRI) inhibits the development of Toll-like receptor-9 signalling-accelerated glomerulonephritis

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The PDL1-PD1 Axis Converts Human T _H 1 Cells into Regulatory T Cells