Targeting of CD45 protein tyrosine phosphatase activity to lipid microdomains on the T cell surface inhibits TCR signaling

We have previously shown that the T-cell protein tyrosine phosphatase (TC-PTP) dephosphorylates the platelet-derived growth factor (PDGF) β-receptor. Here, we show that the increased PDGF β-receptor phosphorylation in TC-PTP knockout (ko) mouse embryonic fibroblasts (MEFs) occurs primarily on the cell surface. The increased phosphorylation is accompanied by a TC-PTP–dependent, monensin-sensitive delay in clearance of cell surface PDGF β-receptors and delayed receptor degradation, suggesting PDGF β-receptor recycling. Recycled receptors could also be directly detected on the cell surface of TC-PTP ko MEFs. The effect of TC-PTP depletion was specific for the PDGF β-receptor, because PDGF α-receptor homodimers were cleared from the cell surface at the same rate in TC-PTP ko MEFs as in wild-type MEFs. Interestingly, PDGF αβ-receptor heterodimers were recycling. Analysis by confocal microscopy revealed that, in TC-PTP ko MEFs, activated PDGF β-receptors colocalized with Rab4a, a marker for rapid recycling. In accordance with this, transient expression of a dominant-negative Rab4a construct increased the rate of clearance of cell surface receptors on TC-PTP ko MEFs. Thus, loss of TC-PTP specifically redirects the PDGF β-receptor toward rapid recycling, which is the first evidence of differential trafficking of PDGF receptor family members.

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Adenosine downregulates DPPIV on HT-29 colon cancer cells by stimulating protein tyrosine phosphatase(s) and reducing ERK1/2 activity via a novel pathway

AJP Cell Physiology ◽

10.1152/ajpcell.00238.2005 ◽

2006 ◽

Vol 291 (3) ◽

pp. C433-C444 ◽

Cited By ~ 25

Author(s):

Ernest Y. Tan ◽

Cynthia L. Richard ◽

Hong Zhang ◽

David W. Hoskin ◽

Jonathan Blay

Keyword(s):

Cell Surface ◽

Phosphatase Activity ◽

Protein Tyrosine Phosphatase ◽

Map Kinases ◽

Tyrosine Phosphatase ◽

Extracellular Fluid ◽

Surface Protein ◽

Receptor Subtypes ◽

Protein Tyrosine ◽

Ht 29

The multifunctional cell-surface protein dipeptidyl peptidase IV (DPPIV/CD26) is aberrantly expressed in many cancers and plays a key role in tumorigenesis and metastasis. Its diverse cellular roles include modulation of chemokine activity by cleaving dipeptides from the chemokine NH2-terminus, perturbation of extracellular nucleoside metabolism by binding the ecto-enzyme adenosine deaminase, and interaction with the extracellular matrix by binding proteins such as collagen and fibronectin. We have recently shown that DPPIV can be downregulated from the cell surface of HT-29 colorectal carcinoma cells by adenosine, which is a metabolite that becomes concentrated in the extracellular fluid of hypoxic solid tumors. Most of the known responses to adenosine are mediated through four different subtypes of G protein-coupled adenosine receptors: A1, A2A, A2B, and A3. We report here that adenosine downregulation of DPPIV from the surface of HT-29 cells occurs independently of these classic receptor subtypes, and is mediated by a novel cell-surface mechanism that induces an increase in protein tyrosine phosphatase activity. The increase in protein tyrosine phosphatase activity leads to a decrease in the tyrosine phosphorylation of ERK1/2 MAP kinase that in turn links to the decline in DPPIV mRNA and protein. The downregulation of DPPIV occurs independently of changes in the activities of protein kinases A or C, phosphatidylinositol 3-kinase, other serine/threonine phosphatases, or the p38 or JNK MAP kinases. This novel action of adenosine has implications for our ability to manipulate adenosine-dependent events within the solid tumor microenvironment.

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Inhibition of T-cell activation by syndecan-4 is mediated by CD148 through protein tyrosine phosphatase activity

European Journal of Immunology ◽

10.1002/eji.201041233 ◽

2011 ◽

Vol 41 (6) ◽

pp. 1794-1799 ◽

Cited By ~ 15

Author(s):

Jin-Sung Chung ◽

Ponciano D. Cruz ◽

Kiyoshi Ariizumi

Keyword(s):

T Cell ◽

Phosphatase Activity ◽

T Cell Activation ◽

Protein Tyrosine Phosphatase ◽

Cell Activation ◽

Tyrosine Phosphatase ◽

Protein Tyrosine

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Astragaloside II triggers T cell activation through regulation of CD45 protein tyrosine phosphatase activity

Acta Pharmacologica Sinica ◽

10.1038/aps.2012.208 ◽

2013 ◽

Vol 34 (4) ◽

pp. 522-530 ◽

Cited By ~ 25

Author(s):

Chun-ping Wan ◽

Li-xin Gao ◽

Li-fei Hou ◽

Xiao-qian Yang ◽

Pei-lan He ◽

...

Keyword(s):

T Cell ◽

Phosphatase Activity ◽

T Cell Activation ◽

Protein Tyrosine Phosphatase ◽

Cell Activation ◽

Tyrosine Phosphatase ◽

Protein Tyrosine

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The roseoloviruses downregulate the protein tyrosine phosphatase PTPRC (CD45)

10.1101/2020.09.29.318709 ◽

2020 ◽

Author(s):

Melissa L. Whyte ◽

Kelsey Smith ◽

Amanda Buchberger ◽

Linda Berg Luecke ◽

Lidya Handayani Tjan ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

T Cell ◽

Cell Surface ◽

Protein Tyrosine Phosphatase ◽

Tyrosine Phosphatase ◽

Human Herpesvirus ◽

Murine Cytomegalovirus ◽

Protein Tyrosine ◽

Infected Cells

AbstractLike all herpesviruses, the roseoloviruses (HHV6A, -6B, and -7) establish lifelong infection within their host, requiring these viruses to evade host anti-viral responses. One common host-evasion strategy is the downregulation of host-encoded, surface-expressed glycoproteins. Roseoloviruses have been shown to evade host the host immune response by downregulating NK-activating ligands, MHC class I, and the TCR/CD3 complex. To more globally identify glycoproteins that are differentially expressed on the surface of HHV6A-infected cells, we performed cell surface capture of N-linked glycoproteins present on the surface of T cells infected with HHV6A, and compared these to proteins present on the surface of uninfected T cells. We found that the protein tyrosine phosphatase CD45 is downregulated in T cells infected with HHV6A. We also demonstrated that CD45 is similarly downregulated in cells infected with HHV-7. CD45 is essential for signaling through the T cell receptor and as such, is necessary for developing a fully functional immune response. Interestingly, the closely related β-herpesviruses human cytomegalovirus (HCMV) and murine cytomegalovirus (MCMV) have also separately evolved unique mechanisms to target CD45. While HCMV and MCMV target CD45 signaling and trafficking, HHV6A acts to downregulate CD45 transcripts.ImportanceHuman herpesviruses-6 and -7 infect essentially 100% of the world’s population before the age of 5 and then remain latent or persistent in their host throughout life. As such, these viruses are among the most pervasive and stealthy of all viruses. Host immune cells rely on the presence of surface-expressed proteins to identify and target virus-infected cells. Here, we investigated the changes that occur to proteins expressed on the cell surface of T cells after infection with human herpesvirus-6A. We discovered that HHV-6A infection results in a reduction of CD45 on the surface of infected cells. Targeting of CD45 may prevent activation of these virus-infected T cells, possibly lengthening the life of the infected T cell so that it can harbor latent virus.

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