Tyrosine Phosphorylation of the CD3-ε Subunit of the T Cell Antigen Receptor Mediates Enhanced Association with Phosphatidylinositol 3-Kinase in Jurkat T Cells

Aós, Isabel de; Metzger, Markus; Exley, Mark A.; Dahl, Charles E.; Misra, Suniti; Zheng, Dexian; Varticovski, Lyuba; Terhorst, Cox; Sancho, Jaime

doi:10.1074/jbc.272.40.25310

Cited by 47 publications

(37 citation statements)

References 53 publications

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“…Because CD3-and CD3-⑀ are tyrosine-phosphorylated upon CD38 cross-linking (Zubiaur et al (28,31) and this paper), and these proteins could interact in a phosphorylationdependent manner with the p85␣ PI 3-kinase (31,79,80), they could target PI 3-kinase to rafts. In addition, binding of PI 3-kinase to the TCR-CD3 per se could up-regulate the PI 3-kinase activity (79,80), presumably by a conformational change as reported previously for other p85-binding proteins (81,82). Other candidate molecules are LAT, Shc, and Cbl, as these molecules bind p85 (83), and are tyrosine-phosphorylated upon CD38 stimulation (Figs.…”

Section: Discussionmentioning

confidence: 99%

CD38 Signaling in T Cells Is Initiated within a Subset of Membrane Rafts Containing Lck and the CD3-ζ Subunit of the T Cell Antigen Receptor

Muñoz

Navarro

Pavón

et al. 2003

Journal of Biological Chemistry

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In this study we present data supporting that most CD38 is pre-assembled in a subset of Brij 98-resistant raft vesicles, which were stable at 37°C, and have relatively high levels of Lck and the CD3-subunit of T cell antigen receptor-CD3 complex in contrast with a Brij 98-soluble pool, where CD38 is associated with CD3-, and Lck is not detected. Our data further indicate that following CD38 engagement, LAT and Lck are tyrosinephosphorylated exclusively in Brij 98-resistant rafts, and some key signaling components translocate into rafts (i.e. Sos and p85-phosphatidylinositol 3-kinase). Moreover, N-Ras results activated within rafts immediately upon CD38 ligation, whereas activated Erk was mainly found in soluble fractions with delayed kinetics respective to Ras activation. Furthermore, full phosphorylation of CD3-and CD3-⑀ only occurs in rafts, whereas partial CD3-tyrosine phosphorylation occurs exclusively in the soluble pool, which correlated with increased levels of c-Cbl tyrosine phosphorylation in the non-raft fractions. Taken together, these results suggest that, unlike the non-raft pool, CD38 in rafts is able to initiate and propagate several activating signaling pathways, possibly by facilitating critical associations within other raft subsets, for example, LAT rafts via its capacity to interact with Lck and CD3-. Overall, these findings provide the first evidence that CD38 operates in two functionally distinct microdomains of the plasma membrane.

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Section: Discussionmentioning

confidence: 99%

CD38 Signaling in T Cells Is Initiated within a Subset of Membrane Rafts Containing Lck and the CD3-ζ Subunit of the T Cell Antigen Receptor

Muñoz

Navarro

Pavón

et al. 2003

Journal of Biological Chemistry

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“…The polymerase chain reaction product was cloned into the XhoI and BamHI sites of the pSR␣ expression vector. The CD8/⑀ construct expressing the extracellular and transmembrane domains of human CD8␣ fused to the cytoplasmic tail of CD3⑀ has been previously described (23) and was a gift from Dr. C. Terhorst.…”

Section: Methodsmentioning

confidence: 99%

“…http://www.jbc.org/ Downloaded from with nucleolin in the central portion, and via the ITAM (C terminus) with ZAP70 and probably other SH2-containing proteins (23,24). Although at first glance it would seem unlikely that the cytoplasmic tail of CD3⑀ interacts with two nuclear proteins, topoisomerase II␤ and nucleolin, the interaction with both proteins might be facilitated by a possible location of CD3⑀ in the inner nuclear membrane (13).…”

Section: Cd3⑀ Interaction With Nucleolin 11177mentioning

confidence: 99%

“…Nucleolin-To determine whether expression of the cytoplasmic tail of CD3⑀ is sufficient to enable nucleolin relocalization, a protein chimera consisting of the cytoplasmic tail of CD3⑀ appended to the transmembrane and extracellular domains of CD8␣ (CD8/⑀) was obtained (23). As a control, a truncated mutant of CD8␣ lacking the cytoplasmic tail was used (CD8t).…”

Section: Expression Of a Protein Chimera Containing The Cytoplasmic Tmentioning

confidence: 99%

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Intracellular Redistribution of Nucleolin upon Interaction with the CD3ε Chain of the T Cell Receptor Complex

Gil

Gutiérrez

Alarcón

2001

Journal of Biological Chemistry

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T cell activation through the antigen receptor (TCR) involves the cytoplasmic tails of the CD3 subunits CD3␥, CD3␦, CD3⑀, and CD3. Whereas the biological significance of the cytoplasmic tails of these molecules is suggested, in part, by their evolutionarily conserved sequences, their interactions with signal transduction molecules are not completely understood. We used affinity chromatography columns of glutathione S-transferase fused to the CD3⑀ cytoplasmic tail to isolate proteins that specifically interact with this subunit. In this way, we identified the shuttling protein nucleolin as a specific CD3⑀-interacting molecule. Using competition studies and affinity chromatography on peptide columns, we were able to identify a central proline-rich sequence as the nucleolin-interacting sequence in CD3⑀. Transfection in COS cells of wild type CD3⑀, but not of nonbinding mutants of CD3⑀, resulted in redistribution of nucleolin from the nucleus and nucleoli to the cytoplasm. This property was transferred to a CD8 protein chimera by appending the cytoplasmic tail of CD3⑀. We also found that nucleolin associated with the TCR complex. This association was increased upon TCR engagement, suggesting that the CD3⑀/nucleolin interaction may have a role in T cell activation.T cells respond to antigen via a polypeptide complex composed of ligand-binding T cell receptor (TCR) 1 ␣ and ␤ chains (or ␥ and ␦ in ␥␦ T cells) and the CD3 subunits CD3␥, CD3␦, CD3⑀, and CD3 (1, 2). Unlike the TCR chains, the CD3 components have long cytoplasmic tails that associate with cytoplasmic signal transduction molecules. This association is mediated at least in part by a double tyrosine-based motif present in a single copy in the CD3␥, CD3␦, and CD3⑀ chains and in three copies in CD3 (3). This motif, named immune-receptor tyrosine-based activation motif (ITAM), becomes tyrosine phosphorylated during T cell activation by the Src family proteintyrosine kinases . Tyrosine phosphorylated ITAM become docking sites for the Syk family proteintyrosine kinase ZAP70 and other signal-transducing molecules. It is well established that antibody-mediated engagement of protein chimeras containing the cytoplasmic tail of either CD3 or CD3⑀ results in T cell activation (7-10). These data indicate that the cytoplasmic tail of one of these subunits can be sufficient to induce T cell activation. Regarding the role of CD3 subunits in T cell activation, most of the attention has been focused on the ITAM. However, the cytoplasmic tails of the CD3 subunits contain other evolutionarily conserved features that suggest ITAM-independent roles for them.The CD3⑀ cytoplasmic tail, highly conserved (11, 12), can be tentatively subdivided into three regions; the N-terminal region contains a basic amino acid cluster, the central region contains a proline-rich sequence, and the C-terminal region contains the ITAM (13). The proline-rich sequence contains the SH3-binding consensus motif XPPXP, and the C-terminal region contains the YXXLXXR endoplasmic reticulum (ER) retention sequ...

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“…These proteins have very short extracellular domains and each intracellular domain contains a conserved protein tyrosine kinase (PTK) recognition motif, termed "Immunoreceptor Tyrosine-based Activation Motif" (ITAM). The associated, disulfide-linked ζ-dimer, sometimes substituted by a ζ-η heterodimer, contains three ITAMs per protein chain (De Aos et al, 1997). ITAMs are substrates for src family PTKs (Iwashima et al, 1994;Weil et al, 1995), and their phosphorylation is a determining initiation event for T cell signaling (Qian et al, 1993).…”

Section: T Helper Cell Activationmentioning

confidence: 99%

Signal Transduction in T Helper Cells: CD4 Coreceptors Exert Complex Regulatory Effects on T Cell Activation and Function

König

Zhou

2004

Current Issues in Molecular Biology

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The immune system provides a highly sophisticated surveillance mechanism to detect diverse antigens and to protect the host organism from invading pathogens and altered cells (e.g., virus-infected and tumor cells). Adaptive immune responses depend on the recognition of antigen by specific antigen receptors that are expressed on the surface of T and B lymphocytes. Helper T cells provide regulatory functions and direct the adaptive immune system to respond appropriately to a particular antigen (i.e., cytotoxic T cell responses against viral infections and tumor cells, humoral responses against extracellular bacteria and parasitic worms). Helper T cells express CD4 coreceptors, which recognize conserved domains on proteins expressed by the class II major histocompatibility complex, the same proteins that present antigen to the T cell receptor. Recent progress in T cell biology has identified multiple regulatory functions of CD4 during thymocyte development and antigen stimulation of mature T helper cells. Signaling pathways induced by engagement of CD4 independently of T cell receptor signaling mediate these regulatory functions. In this review, we discuss the regulation of T cell signaling and emphasize the functional consequences of proper and improper CD4 coreceptor signaling.

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Tyrosine Phosphorylation of the CD3-ε Subunit of the T Cell Antigen Receptor Mediates Enhanced Association with Phosphatidylinositol 3-Kinase in Jurkat T Cells

Cited by 47 publications

References 53 publications

CD38 Signaling in T Cells Is Initiated within a Subset of Membrane Rafts Containing Lck and the CD3-ζ Subunit of the T Cell Antigen Receptor

CD38 Signaling in T Cells Is Initiated within a Subset of Membrane Rafts Containing Lck and the CD3-ζ Subunit of the T Cell Antigen Receptor

Intracellular Redistribution of Nucleolin upon Interaction with the CD3ε Chain of the T Cell Receptor Complex

Signal Transduction in T Helper Cells: CD4 Coreceptors Exert Complex Regulatory Effects on T Cell Activation and Function

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