Cloning of two members of the SIRPα family of protein tyrosine phosphatase binding proteins in cattle that are expressed on monocytes and a subpopulation of dendritic cells and which mediate binding to CD4 T cells

BackgroundWe have previously discovered a relationship between the low expression of protein tyrosine phosphatase, receptor type O (PTPRO) in tumor-infiltrating T cells and immunosuppression. The aim of the present study was to investigate the relationship between decreased PTPRO and increased programmed death ligand 1 (PD-L1) in both the peripheral monocytes and tumor-infiltrating macrophages of human hepatocellular carcinoma (HCC).MethodsThe expression and correlation of all the indices were explored in monocytes and tumor-infiltrating macrophages within both human and mice HCC. The mechanic regulations were studied by using both in vitro and in vivo studies.ResultsWe found a significant decrease in PTPRO in HCC peripheral monocytes that was associated with increased PD-L1 expression in peripheral monocytes and tumor-associated macrophages (TAMs) in HCC. Monocyte PD-L1 and PTPRO therefore could serve as valuable prognostic indicators for post-surgery patients with HCC and were associated with increased T-cell exhaustion (Tim3+T cells). A depletion of PTPRO promoted PD-L1 secretion in both monocytes and macrophages through the JAK2/STAT1 and JAK2/STAT3/c-MYC pathways. Increased IL-6 expression was associated with activation of JAK2/STAT3/c-MYC and with decreased PTPRO expression through the STAT3/c-MYC/miR-25–3 p axis. Monocytes and TAMs showed significantly increased miR-25–3 p expression, which could target the 3′ untranslated region of PTPRO. The miR-25–3 p expression positively correlated with serum IL-6 levels, but inversely correlated with PTPRO in HCC monocytes. IL-6/STAT3/c-MYC activation enhanced in vitro miR-25–3 p transcription and decreased PTPRO, while further promoting PD-L1 secretion. Adoptive cell transfer of c-MYC/miR-25–3 p–modified monocytes promoted tumor growth by downregulating PTPRO and causing a PD-L1–induced immunosuppression in an orthotopic tumor transplantation model.ConclusionsIncreased serum IL-6 downregulated PTPRO expression in HCC monocytes and macrophages by activating STAT3/c-MYC/miR-25–3 p and by further enhancing PD-L1 expression through JAK2/STAT1 and JAK2/STAT3/c-MYC signaling.

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Disruption of Lymphocyte Function and Signaling in CD45–associated Protein–null Mice

Journal of Experimental Medicine ◽

10.1084/jem.187.11.1863 ◽

1998 ◽

Vol 187 (11) ◽

pp. 1863-1870 ◽

Cited By ~ 31

Author(s):

Akio Matsuda ◽

Satoshi Motoya ◽

Shioko Kimura ◽

Renee McInnis ◽

Abby L. Maizel ◽

...

Keyword(s):

Signal Transduction ◽

T Cells ◽

Protein Tyrosine Phosphatase ◽

Tyrosine Kinases ◽

Tyrosine Phosphatase ◽

Antigen Receptor ◽

Lymphocyte Function ◽

Receptor Signaling ◽

Protein Tyrosine ◽

Antigen Receptor Signaling

CD45-AP specifically associates with CD45, a protein tyrosine phosphatase essential for lymphocyte differentiation and antigen receptor–mediated signal transduction. CD45 is thought to mediate antigen receptor signaling by dephosphorylating regulatory tyrosine residues on Src family protein tyrosine kinases such as Lck. However, the mechanism for regulating CD45 protein tyrosine phosphatase activity remains unclear. CD45-AP–null mice were created to examine the role of CD45-AP in CD45-mediated signal transduction. T and B lymphocytes showed reduced proliferation in response to antigen receptor stimulation. Both mixed leukocyte reaction and cytotoxic T lymphocyte functions of T cells were also markedly decreased in CD45-AP–null mice. Interestingly, the interaction between CD45 and Lck was significantly reduced in CD45-AP–null T cells, indicating that CD45-AP directly or indirectly mediates the interaction of CD45 with Lck. Our data indicate that CD45-AP is required for normal antigen receptor signaling and function in lymphocytes.

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Effects of protein tyrosine phosphatase-PEST are reversed by Akt in T cells

Cellular Signalling ◽

10.1016/j.cellsig.2014.08.014 ◽

2014 ◽

Vol 26 (12) ◽

pp. 2721-2729 ◽

Cited By ~ 1

Author(s):

Yutaka Arimura ◽

Kazuhiko Shimizu ◽

Madoka Koyanagi ◽

Junji Yagi

Keyword(s):

T Cells ◽

Protein Tyrosine Phosphatase ◽

Tyrosine Phosphatase ◽

Protein Tyrosine

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Distinct Isoforms of the CD45 Protein-tyrosine Phosphatase Differentially Regulate Interleukin 2 Secretion and Activation Signal Pathways Involving Vav in T Cells

Journal of Biological Chemistry ◽

10.1074/jbc.270.42.24949 ◽

1995 ◽

Vol 270 (42) ◽

pp. 24949-24954 ◽

Cited By ~ 50

Author(s):

Daniel W. McKenney ◽

Hideo Onodera ◽

Linda Gorman ◽

Toshihide Mimura ◽

David M. Rothstein

Keyword(s):

T Cells ◽

Protein Tyrosine Phosphatase ◽

Tyrosine Phosphatase ◽

Interleukin 2 ◽

Signal Pathways ◽

Protein Tyrosine

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Control of Dendritic Cell Migration, T Cell-Dependent Immunity, and Autoimmunity by Protein Tyrosine Phosphatase PTPN12 Expressed in Dendritic Cells

Molecular and Cellular Biology ◽

10.1128/mcb.01369-13 ◽

2013 ◽

Vol 34 (5) ◽

pp. 888-899 ◽

Cited By ~ 29

Author(s):

Inmoo Rhee ◽

Ming-Chao Zhong ◽

Boris Reizis ◽

Cheolho Cheong ◽

André Veillette

Keyword(s):

Dendritic Cells ◽

T Cell ◽

Protein Tyrosine Phosphatase ◽

Tyrosine Phosphatase ◽

Genetically Engineered ◽

Lymphoid Tissues ◽

Peripheral Tissues ◽

Protein Tyrosine

Dendritic cells (DCs) capture and process antigens in peripheral tissues, migrate to lymphoid tissues, and present the antigens to T cells. PTPN12, also known as PTP-PEST, is an intracellular protein tyrosine phosphatase (PTP) involved in cell-cell and cell-substratum interactions. Herein, we examined the role of PTPN12 in DCs, using a genetically engineered mouse lacking PTPN12 in DCs. Our data indicated that PTPN12 was not necessary for DC differentiation, DC maturation, or cytokine production in response to inflammatory stimuli. However, it was needed for full induction of T cell-dependent immune responsesin vivo. This function largely correlated with the need of PTPN12 for DC migration from peripheral sites to secondary lymphoid tissues. Loss of PTPN12 in DCs resulted in hyperphosphorylation of the protein tyrosine kinase Pyk2 and its substrate, the adaptor paxillin. Pharmacological inhibition of Pyk2 or downregulation of Pyk2 expression also compromised DC migration, suggesting that Pyk2 deregulation played a pivotal role in the migration defect caused by PTPN12 deficiency. Together, these findings identified PTPN12 as a key regulator in the ability of DCs to induce antigen-induced T cell responses. This is due primarily to the role of PTPN12 in DC migration from peripheral sites to secondary lymphoid organs through regulation of Pyk2.

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Stat6 and IRS-2 Cooperate in Interleukin 4 (IL-4)-Induced Proliferation and Differentiation but Are Dispensable for IL-4-Dependent Rescue from Apoptosis

Molecular and Cellular Biology ◽

10.1128/mcb.22.1.117-126.2002 ◽

2002 ◽

Vol 22 (1) ◽

pp. 117-126 ◽

Cited By ~ 62

Author(s):

Andrea L. Wurster ◽

Dominic J. Withers ◽

Tohru Uchida ◽

Morris F. White ◽

Michael J. Grusby

Keyword(s):

T Cells ◽

Signaling Pathway ◽

Protein Tyrosine Phosphatase ◽

Tyrosine Phosphatase ◽

Interleukin 4 ◽

Signaling Proteins ◽

Protein Tyrosine ◽

Antiapoptotic Effect ◽

Induced Changes

ABSTRACT Stat6 and IRS-2 are two important signaling proteins that associate with the cytoplasmic tail of the interleukin 4 (IL-4) receptor. Data from numerous in vitro experiments have led to a model for IL-4 signal transduction in which the Stat6 signaling pathway is responsible for the IL-4 induced changes in gene expression and differentiation events, while the IRS-2 signaling pathway provides mitogenic and antiapoptotic signals. In order to determine the relative contributions of these signaling molecules in primary lymphocytes, we have examined IL-4 responses in T cells from mice deficient for either Stat6 or IRS-2 as well as from mice doubly deficient for both genes. Both IRS-2 and, especially, Stat6 are shown to be critically involved in IL-4-induced proliferation of T cells, presumably through the cooperative regulation of the Cdk inhibitor p27kip1. Like Stat6-deficient Th cells, IRS-2-deficient cells are also compromised in their ability to secrete Th2 cytokines, revealing a previously unrecognized role for IRS-2 in Th2 cell development. Although Stat6 and/or IRS-2 expression is required for IL-4-induced proliferative and differentiative responses, both signaling proteins are dispensable for the antiapoptotic effect of IL-4. However, treatment of lymphocytes with a protein tyrosine phosphatase inhibitor is able to block the antiapoptotic effect of IL-4 specifically in Stat6- or IRS-2-deficient cells and not in wild-type cells. Our results suggest that Stat6 and IRS-2 cooperate in promoting both IL-4-induced proliferative and differentiating responses, while an additional signaling mediator that depends on protein tyrosine phosphatase activity contributes to the antiapoptotic activities of IL-4 in primary T cells.

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