The Role of Protein Tyrosine Kinases and Protein Tyrosine Phosphatases in T Cell Antigen Receptor Signal Transduction

Chan, Andrew C.; Desai, Dev M.; Weiss, Arthur

doi:10.1146/annurev.iy.12.040194.003011

Cited by 493 publications

(168 citation statements)

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“…3 In summary, the results presented in this manuscript show that CD45-AP is part of a multimolecular complex that includes the TCR complex, CD4, CD8, CD45, and p56 lck . These associations are mediated at least in part through the ability of CD45-AP to associate with CD45 via its transmembrane domain and with activated Lck molecules via its cytoplasmic region.…”

Section: Association Of Cd45-ap With Tcr Signaling Machinerymentioning

confidence: 64%

“…Activation of T-lymphocytes by antigen is initiated by protein tyrosine phosphorylation (1)(2)(3)(4). Although the T-cell antigen receptor (TCR) 1 and the associated CD3 and subunits are devoid of intrinsic protein tyrosine kinase activity, they can recruit two classes of cytoplasmic protein tyrosine kinases to mediate this response, the Src family and the Syk/Zap-70 family.…”

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confidence: 99%

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Interactions of CD45-associated Protein with the Antigen Receptor Signaling Machinery in T-lymphocytes

Veillette¹,

Soussou²,

Latour³

et al. 1999

Journal of Biological Chemistry

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CD45 is a transmembrane protein tyrosine phosphatase playing an essential role during T-cell activation. This function relates to the ability of CD45 to regulate p56 lck , a cytoplasmic protein tyrosine kinase necessary for T-cell antigen receptor (TCR) signaling. Previous studies have demonstrated that CD45 is constitutively associated in T-lymphocytes with a transmembrane molecule termed CD45-AP (or lymphocyte phosphatase-associated phosphoprotein). Even though the exact role of this polypeptide is unclear, recent analyses of mice lacking CD45-AP have indicated that its expression is also required for optimal T-cell activation. Herein, we wished to understand better the function of CD45-AP. The results of our studies showed that in T-cells, CD45-AP is part of a multimolecular complex that includes not only CD45, but also TCR, the CD4 and CD8 coreceptors, and p56 lck . The association of CD45-AP with TCR, CD4, and CD8 seemed to occur via the shared ability of these molecules to bind CD45. However, binding of CD45-AP to p56 lck could take place in the absence of other lymphoid-specific components, suggesting that it can be direct. Structure-function analyses demonstrated that such an interaction was mediated by an acidic segment in the cytoplasmic region of CD45-AP and by the kinase domain of p56 lck . Interestingly, the ability of CD45-AP to interact with Lck in the absence of other lymphoid-specific molecules was proportional to the degree of catalytic activation of p56 lck . Together, these findings suggest that CD45-AP is an adaptor molecule involved in orchestrating interactions among components of the antigen receptor signaling machinery. Moreover, they raise the possibility that one of the functions of CD45-AP is to recognize activated Lck molecules and bring them into the vicinity of CD45.Activation of T-lymphocytes by antigen is initiated by protein tyrosine phosphorylation (1-4). Although the T-cell antigen receptor (TCR) 1 and the associated CD3 and subunits are devoid of intrinsic protein tyrosine kinase activity, they can recruit two classes of cytoplasmic protein tyrosine kinases to mediate this response, the Src family and the Syk/Zap-70 family. The Src-related enzymes Lck and FynT initiate TCR-mediated signals by phosphorylating a signaling motif in the cytoplasmic domain of CD3 and termed ITAM (for immunoreceptor tyrosine-based activation motif). Following this phosphorylation, the Syk/Zap-70 family kinases are activated through binding of their tandem Src homology 2 (SH2) domains to doubly phosphorylated ITAMs. Together with Src family kinases, Zap-70 and Syk are responsible for subsequent tyrosine phosphorylation of several signal transduction molecules including phospholipase C-␥1, Cbl, Vav, Slp-76, and Lat.CD45 is a 180 -220-kDa transmembrane protein tyrosine phosphatase expressed on all nucleated hemopoietic cells (5, 6). In T-cells it constitutes ϳ10% of all cell surface glycoproteins. Previous studies have shown that CD45 is necessary for T-cell activation because of its ability to promot...

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Section: Association Of Cd45-ap With Tcr Signaling Machinerymentioning

confidence: 64%

mentioning

confidence: 99%

Interactions of CD45-associated Protein with the Antigen Receptor Signaling Machinery in T-lymphocytes

Veillette¹,

Soussou²,

Latour³

et al. 1999

Journal of Biological Chemistry

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“…Recent evidence indicates that specialized membrane domains, including caveolae, are involved in the signaling of other cell surface receptors such as certain growth factor receptors (3,5) and glycosylphosphatidylinositollinked mitogenic receptors (12,44,45). Receptor-domain interactions also may be important for other multichain immune recognition receptors that utilize Src family kinases during their initial signaling steps (46,47).…”

Section: Resultsmentioning

confidence: 99%

Compartmentalized Activation of the High Affinity Immunoglobulin E Receptor within Membrane Domains

Field

Holowka

Baird

1997

Journal of Biological Chemistry

320

344

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The earliest known step in the activation of the high affinity IgE receptor, Fc⑀RI, is the tyrosine phosphorylation of its ␤ and ␥ subunits by the Src family tyrosine kinase, Lyn. We report here that aggregation-dependent association of Fc⑀RI with specialized regions of the plasma membrane precedes its tyrosine phosphorylation and appears necessary for this event. Tyrosine phosphorylation of ␤ and ␥ occurs in intact cells only for Fc⑀RI that associate with these detergent-resistant membrane domains, which are enriched in active Lyn. Furthermore, efficient in vitro tyrosine phosphorylation of Fc⑀RI subunits occurs only for those associated with isolated domains. This association and in vitro phosphorylation are highly sensitive to low concentrations of detergent, suggesting that lipid-mediated interactions with Lyn are important in Fc⑀RI activation. Participation of membrane domains accounts for previously unexplained aspects of Fc⑀RI-mediated signaling and may be relevant to signaling by other multichain immune receptors.The plasma membrane contains specialized regions that have distinct compositions and can serve unique functions in the regulation of cell surface receptor activation. For example, caveolae have been shown to associate with certain signaling proteins (1, 2) and have been implicated in receptor activation (3-6), vesicular transport (7,8), and the uptake of small molecules (9). Compositionally related membrane domains, which lack the invaginated morphology of caveolae as well as the membrane protein caveolin, have also been identified and biochemically separated from caveolae (10). These membrane domains, like caveolae, are resistant to solubilization in nonionic detergents such as Triton X-100, are enriched in sphingolipids and glycosylphosphatidylinositol-linked proteins, and are associated with palmitoyl-anchored signaling molecules including Src family tyrosine kinases (10 -14). Detergent-resistant membrane domains isolated from rat basophilic leukemia (RBL) 1 cells, a mast cell line, contain at least 30% of the cellular Lyn, a Src family tyrosine kinase, and no detectable caveolin (15).Aggregation of Fc⑀RI on mast cells and basophils by multivalent antigens leads to phosphorylation of immunoreceptor tyrosine-based activation motifs within the ␤ and ␥ receptor subunits by . This initiates a signaling cascade culminating in secretion of inflammatory mediators and cytokines that play an important role in the allergic response (20, 21). The molecular mechanism by which aggregation of Fc⑀RI initiates its phosphorylation by Lyn is incompletely understood. Selective binding of Lyn directly to unphosphorylated Fc⑀RI ␤ (22) has been proposed to mediate an initial transphosphorylation of aggregated Fc⑀RI (23), but this does not account for the capacity of Fc⑀RI lacking the ␤ subunit (24, 25) or chimeric receptors containing only the ␥ cytoplasmic tail (26 -28) to become tyrosine-phosphorylated upon aggregation. The involvement of detergent-resistant membrane domains in Fc⑀RI signaling was recently sugge...

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“…T-cell activation is initiated by the engagement of the T-cell receptor (TCR) (Weiss and Littman, 1994;Perlmutter et al, 1993;Chan et al, 1994). This causes a rapid tyrosine phosphorylation of ITAM (immunoreceptor tyrosine-based activation motif) sequences on the TCR associated CD3 and z chains (Weiss and Littman, 1994).…”

Section: Introductionmentioning

confidence: 99%

Stimulation through the T cell receptor leads to interactions between SHB and several signaling proteins

et al. 1998

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Shb is a recently described Src homology 2 (SH2) domain-containing adaptor protein. Here we show that Shb is expressed in lymphoid tissues, and is recruited into signaling complexes upon activation of Jurkat T cells. Grb2 binds proline-rich motifs in Shb via its SH3 domains. As a result, a number of proteins detected in anti-Shb and anti-Grb2 immunoprecipitates are shared, including phosphoproteins of 22, 36/38, 55/57 and 70 kDa. Shb-association with p22, which represents the T cell receptor associated z chain, occurs through the Shb SH2 domain. The central region of Shb binds p36/ 38. Since this interaction was inhibited by phosphotyrosine, this region of Shb is likely to contain a non-SH2 PTB (phosphotyrosine binding) domain. The Shb PTB domain was found to preferentially bind the sequence Asp-Asp-X-pTyr when incubated with a phosphopeptide library. A peptide corresponding to a phosphorylation site in 34 kDa Lnk inhibited association between Shb and p36/38. Overexpression of Shb in Jurkat cells led to increased basal phosphorylation of Shb-associated p36/ 38 and p70 proteins. Inactivation of the Shb SH2 domain by an R522K mutation resulted in a reduced stimulation of tyrosine phosphorylation of several proteins in response to CD3 crosslinking when expressed in Jurkat cells. Together, our results show three distinct domains of Shb all participate in the formulation of multimeric signaling complexes in activated T cells. These results indicate that the Shb protein functions in T cell receptor signaling.

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The Role of Protein Tyrosine Kinases and Protein Tyrosine Phosphatases in T Cell Antigen Receptor Signal Transduction

Cited by 493 publications

References 0 publications

Interactions of CD45-associated Protein with the Antigen Receptor Signaling Machinery in T-lymphocytes

Interactions of CD45-associated Protein with the Antigen Receptor Signaling Machinery in T-lymphocytes

Compartmentalized Activation of the High Affinity Immunoglobulin E Receptor within Membrane Domains

Stimulation through the T cell receptor leads to interactions between SHB and several signaling proteins

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