Human T lymphocytes express a protein-tyrosine kinase homologous to p56LSTRA

Trevillyan, James M.; Lin, Yu; Chen, S.J.; Phillips, Chris; Canna, Cheral; Linna, T. Juhani

doi:10.1016/0167-4889(86)90228-4

Cited by 39 publications

(18 citation statements)

References 31 publications

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“…Therefore, it was of interest to also examine the expression of lck in P13 cells and its variants. When examined by Northern blot analysis using a probe specific for lck (32), the RNA from control P13 cells displayed a high level of a 2.4-kb lck mRNA (Fig. 5A, lane 1).…”

Section: Resultsmentioning

confidence: 99%

Altered expression of protein kinase C, lck, and CD45 in a 12-O-tetradecanoylphorbol-13-acetate-dependent leukemic T-cell variant that expresses a high level of interleukin-2 receptor.

Tchou-Wong¹,

Weinstein²

1992

Mol. Cell. Biol.

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The compound 12-O-tetradecanoylphorbol-13-acetate (TPA) is extremely toxic to the P13 subclone of the Jurkat human T-cell leukemia line. By selecting for growth in the presence of TPA, we have isolated two TPA-resistant variants of these cells, P13-50 and P13-5/A8. Studies of protein kinase C (PKC) enzyme activity, immunoblot analyses, and assays for PKC mRNAs indicate that both of these variants express lower levels of PKC than do the parental P13 cells. We suggest that this protects them from the toxic effects of TPA. The P13-5/A8 cells are of particular interest because not only are they resistant to TPA toxicity but they actually require TPA for optimal growth. These cells have a more profound decrease in PKC expression than do P13-50 cells. In addition, P13-5/A8 cells display very little, if any, surface expression of CD45, a receptor-linked tyrosine protein phosphatase, and lck, a lymphocyte-specific tyrosine kinase. On the other hand, they express a very high level of interleukin-2 receptor. A model is proposed that suggests that these cells are dependent on TPA because they have defects in both the PKC and tyrosine kinase signal transduction pathways, and that TPA compensates for these defects by providing a strong stimulus to the residual level of PKC. This variant may be useful for studying the interactions between tyrosine kinase and PKC pathways in controlling the various functions of T lymphocytes.

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Section: Resultsmentioning

confidence: 99%

Altered expression of protein kinase C, lck, and CD45 in a 12-O-tetradecanoylphorbol-13-acetate-dependent leukemic T-cell variant that expresses a high level of interleukin-2 receptor.

Tchou-Wong¹,

Weinstein²

1992

Mol. Cell. Biol.

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“…Murine T cells possess relatively high levels of PTK activity, and distinct patterns of tyrosine phosphorylation have been noted in T and B cells (19)(20)(21)(22)(23)(24)(25). In particular, a protein kinase termed pp56LSTRA/lck has been identified in murine T cells (26,27) and, recently, in human T lymphocytes (28)(29)(30). The rather dramatic decrease of ppS6lck within T cells after activation is suggestive of an importance ofthis enzyme in the activation process (31).…”

mentioning

confidence: 99%

The CD4 receptor is complexed in detergent lysates to a protein-tyrosine kinase (pp58) from human T lymphocytes.

Rudd

Trevillyan

Dasgupta

et al. 1988

Proc. Natl. Acad. Sci. U.S.A.

654

324

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The CD4 (T4) antigen is a cell-surface glycoprotein that is expressed predominantly on the surface ofhelper T cells and has been implicated in the regulation of T-cell activation and in the associative recognition of class II antigens of the major histocompatibility complex. In addition, the CD4 antigen appears to serve as a receptor for the human immunodeficiency virus (HIV). An important question has been whether the CD4 receptor is linked to an intracellular mediator that could regulate the activation of the CD4+ subset. In this paper, we provide preliminary evidence that the CD4 receptor is complexed in detergent lysates to a protein-tyrosine kinase (PTK) of 55-60 kDa, which is expressed specifically in T cells.The PTK is the human analogue of the murine pp56ISTRA (ppS6Ick) and has significant homology with c-src, c-yes, and other members of the src family. The identification of the PTK associated with CD4 receptor was made by use of an antiserum to a synthetic peptide that was deduced from the DNA sequence of PTK. Two-dimensional nonequilibrium pH gradient gel electrophoresis/NaDodSO4/PAGE revealed the kinase to focus as a heterogeneous collection of spots in the pH range of 4.0-5.0. Furthermore, in vitro phosphorylation revealed the phosphorylation of two additional polypeptides at 40 and 80 kDa, in addition to the autophosphorylation of the PIK at 55-60 kDa.The potential importance of the association between the CD4 receptor and the PTK of T cells is discussed in relation to T-cell activation and HIV infectivity.The CD4 (T4) antigen is a polypeptide of 55 kDa that is expressed predominately on the surface of helper T cells and has been implicated in association with the T3 (CD3)-Ti complex in the recognition of class II antigens of the major histocompatibility complex (1, 2). The CD4 antigen also appears to serve as a receptor for the human immunodeficiency virus (HIV) [the acquired immunodeficiency syndrome (AIDS) virus] (3-5). Structurally, the CD4 antigen is a member of the immunoglobulin superfamily (6) and, as such, appears capable of regulating the proliferation of the CD4 subset of T cells (7)(8)(9)(10)(11). Monoclonal antibodies to the CD4 antigen were initially reported to inhibit specific T-cell function by reducing the strength of interaction of the T cell with its target (1, 2, 7). However, it also appears that monoclonal antibodies to the CD4 receptor can inhibit or potentiate the activation of T lymphocytes in a manner independent of the recognition of HLA-D region antigens (8)(9)(10)(11). The inhibitory effect of antibodies to CD4 appears to preferentially influence the T4+2H4+ subset within the CD4 population, a subset defined by the differential expression of the L-C/T200 (CD45) antigens (12,13 Tyrosine phosphorylation is thought to be a relatively rare modification to proteins; however, the past few years have seen a rapidly expanding number of retroviral oncogenes and cellular receptors within the src family. These include the retroviral oncogenes such as v-abl, v-erb, v-fes/...

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“…Its product, p561ck, is expressed almost exclusively in lymphoid cells and tissues (6,22,28,41,47). Like other protein tyrosine kinases, p56'ck is thought to play a role in the generation of growth regulatory signals.…”

mentioning

confidence: 99%

Cross-linking of T-cell surface molecules CD4 and CD8 stimulates phosphorylation of the lck tyrosine protein kinase at the autophosphorylation site.

Luo¹,

Sefton²

1990

Mol. Cell. Biol.

155

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pS6kk, a lymphocyte-specific tyrosine protein kinase, binds to the cytoplasmic tails of the T-cell surface molecules CD4 and CD8. Cross-linking of CD4 expressed on the surface of murine thymocytes, splenocytes, and CD4+ T-cell lines induced tyrosine phosphorylation of p56kk dramatically. Cross-linking of CD8 stimulated tyrosine phosphorylation of p56kk strongly in murine L3 and GA4 cells, slightly Tyr-394 was the predominant site of increased tyrosine phosphorylation in two leukemic cell lines. In the other two cell lines, the phosphorylation of both Tyr-394 and an inhibitory site, Tyr-505, was found to increase. In contrast to cross-linking with antibodies, no striking increase in the tyrosine phosphorylation of ps6ck was stimulated by antigenic stimulation. Therefore, the effect of antibody-induced aggregation of CD4 and CD8 on the tyrosine phosphorylation of p56kk differs, at least quantitatively, from what occurs during antigen-inducedIck is a member of the src family of genes that encode cytoplasmic protein tyrosine kinases. Its product, p561ck, is expressed almost exclusively in lymphoid cells and tissues (6,22,28,41,47). Like other protein tyrosine kinases, p56'ck is thought to play a role in the generation of growth regulatory signals. p561ck binds to the cytoplasmic tails of the T-cell surface molecules CD4 and CD8 in both human and murine T cells (35,38,43,50). Its association with CD4 and CD8 suggests that it may play a role in a signal transduction pathway during T-cell activation or T-cell maturation.CD4 and CD8 bind to class II and class I major histocompatibility proteins, respectively, during antigen-induced T-cell activation (8,11,(30)(31)(32) and during T-cell maturation (9, 21, 37). In addition to increasing adhesion between T cells and antigen-presenting cells, several lines of evidence suggest the involvement of CD4 and CD8 in transducing growth regulatory signals. It has been demonstrated that a truncated form of CD4 that is missing the cytoplasmic domain is less effective than wild-type CD4 at enhancing interleukin-2 production by T cells (39). In addition, studies with CD8a', a form of CD8 lacking most of the cytoplasmic tail, have demonstrated that the cytoplasmic domain of CD8 is also required for antigen-induced T-cell activation (50). The cytoplasmic domains of CD4 and CD8 are therefore likely to be involved in positive signaling during T-cell activation.Since it is the cytoplasmic tails of CD4 and CD8 with which p561ck interacts (38, 50), the inability of these truncated forms of CD4 and CD8 to enhance T-cell activation by antigen suggests that p561ck is involved in positive signaling during T-cell activation.Evidence for negative signaling through CD4, however, * Corresponding author.comes from the observation that treatment of cells with anti-CD4 antibody, such as GK1.5, blocks Ca2" influx at an early stage of T-cell activation (33, 40) and inhibits both antigen-stimulated and lectin-induced interleukin-2 production (2, 33, 48). It is possible, therefore, that pS6lck can also pla...

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Human T lymphocytes express a protein-tyrosine kinase homologous to p56LSTRA

Cited by 39 publications

References 31 publications

Altered expression of protein kinase C, lck, and CD45 in a 12-O-tetradecanoylphorbol-13-acetate-dependent leukemic T-cell variant that expresses a high level of interleukin-2 receptor.

Altered expression of protein kinase C, lck, and CD45 in a 12-O-tetradecanoylphorbol-13-acetate-dependent leukemic T-cell variant that expresses a high level of interleukin-2 receptor.

The CD4 receptor is complexed in detergent lysates to a protein-tyrosine kinase (pp58) from human T lymphocytes.

Cross-linking of T-cell surface molecules CD4 and CD8 stimulates phosphorylation of the lck tyrosine protein kinase at the autophosphorylation site.

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