The CD4/CD8:p56 lck complex in T lymphocytes: a potential mechanism to regulate T-cell growth (original) (raw)
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Proceedings of the …, 1989
Many mammalian receptors have been found to regulate cell growth by virtue of a protein-tyrosine kinase domain in their cytoplasmic tail. We recently described an association of the CD4 antigen with a T-cell-specific proteintyrosine kinase (p56"c"; formerly termed pp58lck; EC 2.7.1.112). This interaction represents a potential mechanism by which T-cell growth may be regulated and offers a model by which other members of the src family (products of c-src, c-yes,
European Journal of Immunology, 1989
Human T cells can be activated and induced to proliferate through either the antigen-specific receptor complex (TcR-CD3) or the CD2 surface molecule. Following stimulation, both serine and tyrosine phosphorylation of cellular protein have been demonstrated to occur. P S~"~, a protein tyrosine kinase associated to the inner face of the plasma membrane, is almost exclusively expressed in lymphoid cells, especiallyTcel1s.Within minutes after activation of a human Tcell-derived line (Jurkat) via stimulation of either the TcR-CD3 complex or the CD2 glycoprotein, we observed a hyperphorphosylation of p56Ick. A concomitant shift to a higher molecular weight in sodium dodecyl sulfatepolyacrylamide gel was also observed. Similar changes were obtained with phorbol 12-myristate 13-acetate. Tryptic phosphopeptide analysis of the hyperphosphorylated form of pS6lck yielded new phosphorylated sites in serine residues and an increased tyrosine phosphorylation. These results suggest that pS6Ick may be intimately connected to the signaling pathway in T cell activation.
Phosphorylation of serine 59 of p56lck in activated T cells
The Journal of biological chemistry, 1993
p56lck, a member of the src family of non-receptor protein tyrosine kinases, is expressed almost exclusively in cells of lymphoid origin. Recent evidence has implicated p56lck in a critical role both in T cell development and activation. A variety of T cell stimuli induce a shift in the electrophoretic mobility of p56lck from an apparent molecular mass of 56 kDa (p56lck) to 60 kDa (p60lck). This shift in electrophoretic mobility correlates with an increase in the phosphoserine content of the p60lck. We have shown that both 4 alpha-phorbol 12 beta-myristate acetate and OKT3 treatment of Jurkat cells, as well as 4 alpha-phorbol 12 beta-myristate acetate treatment of 171.CD4 and LSTRA cells, induced phosphorylation of serine-59 on p56lck in vivo, which correlated with the shift to p60lck. We also demonstrated that the same serine residue could be phosphorylated in vitro with mitogen-activated protein kinases and that this event was capable of reducing p56lck activity in vitro. Combined...
Association of CD8 with p56lck is required for early T cell signalling events
The EMBO Journal, 1991
The human CD8 glycoprotein functions as a co-receptor during T cell activation by both binding to MHC class I and transducing a transmembrane signal. The ability of CD8 to transduce a signal is mediated in part by its association with the protein tyrosine kinase p56kk. Using a panel of human CD8a mutants, we demonstrated that the presence of a functional p56kk binding site is required for the early signalling events transduced by CD8, including increased [Ca2+]i and protein tyrosine phosphorylation. In addition, our results demonstrate that wild-type and all mutant forms of CD8a have an inhibitory effect on signal transduction after CD3-CD3 or CD3-CD4 crosslinking when transfected into the (CD3+, CD4+, CD8-) H9 T cell line, suggesting that intermolecular associations of CD8, independent of its association with p56kk, are responsible for this effect. Signalling through CD4 or CD8 in a double positive thymocyte may therefore be different than in a single positive thymocyte or mature T cell.
European Journal of Immunology, 1992
T cell activation by triggering the T cell receptor (TcR)-CD3 complex leads to a dramatic increase in tyrosine phosphorylation of multiple cellular proteins. To date, there has been no direct evidence on the identity of the tyrosine kinase activity implicated in this signaling pathway. In this study, we demonstrate that activation of human T cells with anti-CD3 monoclonal antibody increases tyrosine kinase activity of p56jCk. This extends our previous findings which demonstrated the involvement of pS61ck kinase activity in the CD2 signal transduction pathway. The results from peripheral blood lymphocytes and Jurkat cell line showed in both cases an early and transient change in the specific activity of p56lckk, followed by a shift to a higher apparent molecular mass. Therefore, to test directly the role of TcR-CD3 in CDZinduced activation of p56lck, we utilized mutant variants of the Jurkat cell line lacking in cell surface TcR-CD3. We found that cell surface expression of TcR-CD3 is not required for the activation of p561Ck via CD2 but is necessary for the appearance of the reduced-electrophoreticmobility form of p561ck observed after CD2 triggering. By isolating CD45mutants from Jurkat cells, we observed that surface expression of the tyrosine phosphatase CD45 is required in order to increase p56lCk activity following CD2 stimulation, while CD44nduced activation of the kinase remained unchanged. These data provide evidence for a specific functional linkage between CD2 and p561ck, in which CD45 may play an essential role.
Molecular and Cellular Biology, 1990
We report that the cytoplasmic domains of the T-lymphocyte glycoproteins CD4 and CD8 alpha contain short related amino acid sequences that are involved in binding the amino-terminal domain of the intracellular tyrosine protein kinase, p56lck. Transfer of as few as six amino acid residues from the cytoplasmic domain of the CD8 alpha protein to the cytoplasmic domain of an unrelated protein conferred p56lck binding to the hybrid protein in HeLa cells. The common sequence motif shared by CD4 and CD8 alpha contains two cysteines, and mutation of either cysteine in the CD4 sequence eliminated binding of p56lck.p56lck also contains two cysteine residues within its CD4-CD8 alpha-binding domain, and both are critical to the interaction with CD4 or CD8 alpha. Because the interaction does not involve disulfide bond formation, a metal ion could stabilize the complex.
Evidence for Protein Tyrosine Kinase Involvement in CD6Induced T Cell Proliferation
Cellular Immunology, 1995
action between the T cell and antigen that is expressed in conjunction with either MHC class I or class II mole-Several studies have demonstrated that addition of cules on an antigen-presenting cell. However, the sigsoluble anti-CD6 mAbs to 12-O-tetradecanoylphorbol nals induced through the TCR during antigen-specific
The Journal of Cell Biology, 1992
The lymphocyte glycoprotein CD4 is constitutively internalized and recycled in nonlymphoid cells, but is excluded from the endocytic pathway in lymphocytic cells (Pelchen-Matthews, A., J. E. Armes, G. Griffiths, and M. Marsh. 1991. J. Exp. Med. 173 : 575-587) . Inhibition of CD4 endocytosis is dependent on CD4 expressing an intact cytoplasmic domain and is only observed in cells where CD4 can interact with the protein tyrosine kinase p56'ck, a member of the src gene family. We have expressed p56'ck, p60-s-, or chimeras of the two proteins in CD4-transfected NIH-3T3 or HeLa cells . Immunoprecipitation of CD4 and in vitro kinase assays showed that p56'ck and the lck/ src chimera, which contains the NH2 terminus of p56kk, can associate with CD4 . In contrast, p60-and the src/lck chimera, which has the NH2 terminus T HE cell surface glycoprotein CD4, which is expressed primarily on helper T lymphocytes, recognizes nonpolymorphic regions of the class II major histocompatibility complex ((MHC)', for review see references 34, 41). CD4 is believed to participate in T cell activation by antigen in two ways. First, it can act as an accessory molecule to the T cell receptor/CD3 complex, facilitating adhesion between T cells andantigen-presenting cells (9, 42) . Second, it can be directly involved in signal transduction via the protein tyrosine kinase p56k* (for review see reference 43) . In humans, CD4 is also expressed on cells of the macrophage/ monocyte lineage, dendritic cells, and eosinophils, where it may act as the receptor for lymphocyte chemoattractant factor (7) . In addition, CD4 acts as a cellular receptor for the human immunodeficiency viruses (HIV-1 and -2; for reviews see references 41, 47) . The structure ofthe CD4 mole-The present address and address for correspondence for A . Pelchen-Matthews and M . Marsh is