Rescue of Signaling by a Chimeric Protein Containing the Cytoplasmic Domain of CD45

Hovis, Robin R.; Donovan, Jerald A.; Musci, Michael A.; Motto, David G.; Goldman, Frederick D.; Ross, Scott R.; Koretzky, Gary A.

doi:10.1126/science.8475387

Cited by 106 publications

(81 citation statements)

References 37 publications

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“…Furthermore, transfection of the cytoplasmic domain of CD45 (containing tyrosine phosphatase activity) into CD45-negative cells was also able to moderately restore the migratory response, suggesting that CD45 phosphatase activity is important for mediating CXCL12-induced chemotactic signaling. The cytoplasmic domain of CD45 has also been shown to be required for TCR-mediated signaling events (22,23).…”

Section: Discussionmentioning

confidence: 99%

“…J45/CH11 (expressing a chimeric protein containing the extracellular and transmembrane domains of HLA-A2 and the cytoplasmic domain of CD45), its control J45/A2 (expressing the extracellular and transmembrane domains of HLA-A2), and J45/LB3 (J45.01 transfectants expressing normal human CD45) were kindly provided by Dr. Gary A. Koretzky (University of Pennsylvania School of Medicine) and Dr. Eric J. Brown (University of California, San Francisco, CA) and have been described before (23). All the cell lines were cultured at 37°C in 5% CO 2 in RPMI 1640 with 10% fetal calf serum, 2 mM glutamine, 50 g/ml penicillin, and 50 g/ml streptomycin.…”

Section: Reagents Andmentioning

confidence: 99%

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Differential Regulation of CXCR4-mediated T-cell Chemotaxis and Mitogen-activated Protein Kinase Activation by the Membrane Tyrosine Phosphatase, CD45

Fernandis¹,

Cherla²,

Ganju

2003

Journal of Biological Chemistry

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The chemokine receptor CXCR4 and its cognate ligand, stromal cell-derived factor-1␣ (CXCL12), regulate lymphocyte trafficking and play an important role in host immune surveillance. However, the molecular mechanisms involved in CXCL12-induced and CXCR4-mediated chemotaxis of T-lymphocytes are not completely elucidated. In the present study, we examined the role of the membrane tyrosine phosphatase CD45, which regulates antigen receptor signaling in CXCR4-mediated chemotaxis and mitogen-activated protein kinase (

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Section: Discussionmentioning

confidence: 99%

Section: Reagents Andmentioning

confidence: 99%

Differential Regulation of CXCR4-mediated T-cell Chemotaxis and Mitogen-activated Protein Kinase Activation by the Membrane Tyrosine Phosphatase, CD45

Fernandis¹,

Cherla²,

Ganju

2003

Journal of Biological Chemistry

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“…J45/CH11 (expressing a chimeric protein containing the extracellular and transmembrane domains of HLA-A2 and the phosphatase domain of CD45), its control J45/A2 (expressing the extracellular and transmembrane domains of HLA-A2), and J45/LB3 (J45.01 transfectants expressing normal human CD45) were kindly provided by Dr. Gary A. Koretzky (University of Pennsylvania School of Medicine) and Dr. Eric J. Brown (Uni-versity of California, San Francisco, CA), respectively, and have been described previously (27,36). All cell lines were cultured at 37°C in 5% CO 2 in RPMI 1640 medium containing 10% fetal calf serum, 2 mM glutamine, 50 g/ml penicillin, and 50 g/ml streptomycin.…”

Section: Methodsmentioning

confidence: 99%

“…Here, we chose to examine the structural components of CD45 that are important for HIV gp120-induced apoptosis. For this purpose, we analyzed the ability of transfectants expressing hybrid CD45 cDNA to restore gp120-induced apoptosis (36). As shown in Fig.…”

Section: The Extracellular Domain and The Intracellular Phosphatase Dmentioning

confidence: 99%

HIV-1 gp120-mediated Apoptosis of T Cells Is Regulated by the Membrane Tyrosine Phosphatase CD45

Anand

Ganju

2006

Journal of Biological Chemistry

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The molecular mechanism of the human immunodeficiency virus type 1 (HIV-1) gp120-induced apoptosis of bystander T cells is not well defined. Here, we demonstrate that CD45, a key component of the T cell receptor pathway, plays a crucial role in apoptosis induced by HIV-1 gp120. We observed that HIV-1 gp120-induced apoptosis was significantly reduced in a CD45-deficient cell line and that reconstitution of CD45 in these cells restored gp120-induced apoptosis. However, expression of a chimeric protein containing only the intracellular phosphatase domain was not able to restore the apoptotic function in the CD45-negative clone, indicating an important role for the extracellular domain of CD45 in this function. The role of CD45 in gp120-induced apoptosis was further confirmed in T cell lines and peripheral blood mononuclear cells using a selective CD45 inhibitor as well as CD45-specific small interfering RNA. We also observed that gp120 treatment induced CD45 association with the HIV coreceptor CXCR4. Further elucidation of downstream signaling events revealed that CD45 modulates HIV-1 gp120-induced apoptosis by regulating Fas ligand induction and activation of the phosphoinositide 3-kinase/Akt pathway. These results suggest a novel CD45-mediated mechanism for the HIV envelope-induced apoptosis of T cells. The depletion of CD4ϩ T lymphocytes is a central pathogenic feature of human immunodeficiency virus type 1 (HIV-1) 2 infection and is largely responsible for the profound immunodeficiency characteristic of the late stages of HIV disease (1). Multiple mechanisms have been shown to contribute to the HIV-1-associated loss of CD4 ϩ T cells in HIV-1-infected individuals, among which the HIV-1-induced apoptosis of bystander uninfected cells is considered to be the most important (2-5). Several virally encoded proteins, including the envelope protein gp120, Tat, and Vpr, have been implicated in this process (3,6,7). Cumulative data demonstrate a major role for the HIV envelope glycoprotein in the death of uninfected lymphocytes (8, 9). The presence of measurable amounts of circulating soluble gp120 in HIV-infected subjects and the accumulation of a high concentration of envelope glycoproteins in lymphoid tissues underscore the potential for the envelope to contribute to T cell dysfunction (10, 11). A number of studies have indicated that HIV-1 gp120-induced apoptosis could represent an exacerbation of activation-induced cell death (12, 13). In fact, circulating T lymphocytes in HIV-1-infected patients are characterized by a high degree of immune activation (14, 15). Although immune activation may modulate HIV-mediated apoptosis, the molecular mechanisms involving the cross-talk between the T cell receptor (TCR) pathway and HIV-1 gp120 and leading to T cell loss are still unclear. Because the proteintyrosine phosphatase CD45 plays an essential role in TCR signaling (16 -18), it seemed reasonable to speculate that it may play a key role in HIV envelope-mediated apoptosis. CD45 is a transmembrane protein-tyrosine phosphatas...

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“…While the in vitro phosphatase activity of CD45 has long been considered unchanged, CD45 in human T cells and T cell leukaemic lines has been found to be phosphorylated at tyrosine residues by phorbol ester, lectin, and anti-CD3 antibodies [49,50]. Accumulating evidence suggests that the in vitro catalytic activity of CD45 is regulated by ligand binding, phosphorylation, or other covalent modification [27,44,[50][51][52][53]. Phorbol esters, by activating PKC and Ca 2þ ionophore, have been shown to down-regulate PTPase activity [25], while direct binding of the cytoplasmic domain of CD45 to cytoskeletal proteins such as by fodrin, spectrin, or PHA, and phosphorylation of Y1193 of CD45 by p50 csk , up-regulate its activity [28,[52][53][54].…”

Section: Discussionmentioning

confidence: 99%

Reduced protein tyrosine phosphatase (PTPase) activity of CD45 on peripheral blood lymphocytes in patients with systemic lupus erythematosus (SLE)

Takeuchi

Pang

Amano

et al. 1997

Clinical and Experimental Immunology

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SUMMARYTo disclose the mechanism of aberrant function of peripheral blood lymphocytes (PBL) in SLE, we focused on the catalytic function of CD45, and determined the CD45 PTPase activity in SLE patients. The sample population consisted of 32 SLE patients with different disease activity. PTPase activity of cell lysates immunoprecipitated by anti-CD45 MoAb was assayed against phosphotyrosine analogue PNPP, followed by measuring the release of para-nitro phenol at 410 nm. CD45 PTPase activity of PBL was significantly decreased in SLE patients, compared with that of normal controls and patients with systemic sclerosis (964 Ϯ 265, 1202 Ϯ 172, 1210 Ϯ 125, respectively; SLE versus normal, P < 0 . 05). It was correlated with SLE Disease Activity Index (SLEDAI) score (r ¼ 0 . 597, P ¼ 0 . 0006), but not with the dose of prednisolone (r ¼ 0 . 214, P ¼ 0 . 2657), indicating that CD45 PTPase activity became reduced when the disease was active, but it was not affected by prednisolone. Moreover, it was not corrected by in vitro culture with or without stimulation. The expression of CD45 on PBL was comparable between normal and SLE, raising a possibility that it may be due to aberrant regulation of catalytic function of CD45 in SLE. Given the evidence that tyrosine phosphorylation of cellular proteins by tyrosine kinases and phosphatases is one of the key biochemical events in the signal transduction pathway, the decreased CD45 PTPase activity in SLE may account for the defective signal transduction via TCR/CD3, leading to dysregulated effector function of the lymphocytes.

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Rescue of Signaling by a Chimeric Protein Containing the Cytoplasmic Domain of CD45

Cited by 106 publications

References 37 publications

Differential Regulation of CXCR4-mediated T-cell Chemotaxis and Mitogen-activated Protein Kinase Activation by the Membrane Tyrosine Phosphatase, CD45

Differential Regulation of CXCR4-mediated T-cell Chemotaxis and Mitogen-activated Protein Kinase Activation by the Membrane Tyrosine Phosphatase, CD45

HIV-1 gp120-mediated Apoptosis of T Cells Is Regulated by the Membrane Tyrosine Phosphatase CD45

Reduced protein tyrosine phosphatase (PTPase) activity of CD45 on peripheral blood lymphocytes in patients with systemic lupus erythematosus (SLE)

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