The structure, regulation, and function of ZAP‐70

Au-Yeung, Byron B; Deindl, Sebastian; Hsu, Lih-Yun; Palacios, Emil H.; Levin, Susan E.; Kuriyan, John; Weiss, Arthur

doi:10.1111/j.1600-065x.2008.00753.x

Cited by 184 publications

(178 citation statements)

References 76 publications

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“…This activation step triggers the recruitment of ZAP70 (9), which itself is activated by phosphorylation by the TCR-proximal Src family kinase Lck (8). Active ZAP70 subsequently phosphorylates two critically important adaptor proteins, linker of activated T cells (LAT) and Src homology-2 domain-containing leukocyte protein of 76 kDa (SLP-76) (10). LAT facilitates the formation of several multiprotein complexes and acts as nucleation center for T cell signal transduction (11).…”

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confidence: 99%

HIV-1 Nef Limits Communication between Linker of Activated T Cells and SLP-76 To Reduce Formation of SLP-76–Signaling Microclusters following TCR Stimulation

Abraham

Bankhead

Pan

et al. 2012

The Journal of Immunology

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Signal initiation by engagement of the TCR triggers actin rearrangements, receptor clustering, and dynamic organization of signaling complexes to elicit and sustain downstream signaling. Nef, a pathogenicity factor of HIV, disrupts early TCR signaling in target T cells. To define the mechanism underlying this Nef-mediated signal disruption, we employed quantitative single-cell microscopy following surface-mediated TCR stimulation that allows for dynamic visualization of distinct signaling complexes as microclusters (MCs). Despite marked inhibition of actin remodeling and cell spreading, the induction of MCs containing TCR-CD3 or ZAP70 was not affected significantly by Nef. However, Nef potently inhibited the subsequent formation of MCs positive for the signaling adaptor Src homology-2 domain-containing leukocyte protein of 76 kDa (SLP-76) to reduce MC density in Nef-expressing and HIV-1–infected T cells. Further analyses suggested that Nef prevents formation of SLP-76 MCs at the level of the upstream adaptor protein, linker of activated T cells (LAT), that couples ZAP70 to SLP-76. Nef did not disrupt pre-existing MCs positive for LAT. However, the presence of the viral protein prevented de novo recruitment of active LAT into MCs due to retargeting of LAT to an intracellular compartment. These modulations in MC formation and composition depended on Nef’s ability to simultaneously disrupt both actin remodeling and subcellular localization of TCR-proximal machinery. Nef thus employs a dual mechanism to disturb early TCR signaling by limiting the communication between LAT and SLP-76 and preventing the dynamic formation of SLP-76–signaling MCs.

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HIV-1 Nef Limits Communication between Linker of Activated T Cells and SLP-76 To Reduce Formation of SLP-76–Signaling Microclusters following TCR Stimulation

Abraham

Bankhead

Pan

et al. 2012

The Journal of Immunology

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“…Syk and ZAP-70 are members of a tyrosine kinase family one or both of which are expressed in most hematopoietic cells (1)(2)(3)(4)(5). Structurally Syk/ZAP-70 consists of two Src-homology 2 domains (SH2) 3 and a kinase domain followed by a short COOH-terminal extension (tail).…”

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Tyrosines in the Carboxyl Terminus Regulate Syk Kinase Activity and Function

Castro

Zhang

Jamur

et al. 2010

Journal of Biological Chemistry

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The Syk tyrosine kinase family plays an essential role in immunoreceptor tyrosine-based activation motif (ITAM) signaling. The binding of Syk to tyrosine-phosphorylated ITAM subunits of immunoreceptors, such as Fc⑀RI on mast cells, results in a conformational change, with an increase of enzymatic activity of Syk. This conformational change exposes the COOH-terminal tail of Syk, which has three conserved Tyr residues (Tyr-623, Tyr-624, and Tyr-625 of rat Syk). To understand the role of these residues in signaling, wild-type and mutant Syk with these three Tyr mutated to Phe was expressed in Syk-deficient mast cells. There was decreased Fc⑀RI-induced degranulation, nuclear factor for T cell activation and NFB activation with the mutated Syk together with reduced phosphorylation of MAP kinases p38 and p42/44 ERK. In non-stimulated cells, the mutated Syk was more tyrosine phosphorylated predominantly as a result of autophosphorylation. In vitro, there was reduced binding of mutated Syk to phosphorylated ITAM due to this increased phosphorylation. This mutated Syk from non-stimulated cells had significantly reduced kinase activity toward an exogenous substrate, whereas its autophosphorylation capacity was not affected. However, the kinase activity and the autophosphorylation capacity of this mutated Syk were dramatically decreased when the protein was dephosphorylated before the in vitro kinase reaction. Furthermore, mutation of these tyrosines in the COOH-terminal region of Syk transforms it to an enzyme, similar to its homolog ZAP-70, which depends on other tyrosine kinases for optimal activation. In testing Syk mutated singly at each one of the tyrosines, Tyr-624 but especially Tyr-625 had the major role in these reactions. Therefore, these results indicate that these tyrosines in the tail region play a critical role in regulating the kinase activity and function of Syk.Syk and ZAP-70 are members of a tyrosine kinase family one or both of which are expressed in most hematopoietic cells (1-5). Structurally Syk/ZAP-70 consists of two Src-homology 2 domains (SH2) 3 and a kinase domain followed by a short COOH-terminal extension (tail). The inter-SH2 domain is located between the NH 2 -terminal SH2 (SH2-N) and COOHterminal SH2 (SH2-C), whereas the linker region is between the SH2-C and the kinase domains (6, 7). An alternatively spliced form of Syk, termed SykB, lacks a 23-amino acid sequence in the linker domain (8). Although both isoforms are expressed in immune cells such as the RBL-2H3 rat mast cell line, Syk is more efficient than SykB in immunoreceptor signaling (8,9). Syk is expressed in B cells, mast cells, immature T cells, and platelets, whereas ZAP-70 is in T cells and natural killer cells (3, 10). Syk and ZAP-70 are essential for signal transduction from cell surface immunoreceptors (10 -12). These receptors on many hematopoietic cells such as T, B, and mast cells have subunits, which contain a sequence named the immunoreceptor tyrosine-based activation motif (ITAM) which contains two tyrosine residues (13...

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“…Whether Syk might constitute a promising new drug target in PTCL will have to await larger, future studies. Given that Syk and ZAP-70 may partially substitute each other in normal and neoplastic B and T cells 26,30,31 we investigated whether Syk and ZAP-70 expression was mutually exclusive in CD30 + T-cell lymphoproliferations. However, this turned out not to be the case.…”

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confidence: 99%

“…Only 16% of primary cutaneous CD30 + Tcell lymphoproliferative disorders, but more than half of the systemic ALCL displayed no or only very weak ZAP-70 expression. Interestingly, Syk, a protein kinase molecularly and functionally highly related to ZAP-70 and normally expressed in B cells, [26][27][28][29][30][31] was aberrantly expressed in 29% of ALK -systemic ALCL, 64% ALK + systemic ALCL, and 32% of primary cutaneous CD30 + T-cell lymphoproliferative disorders, while all 20 PTCL-NOS remained negative. Thus, for unknown reasons, we were unable to reproduce the results of Feldmann et al 32 who detected Syk-positivity in nearly 100% of CD30 + T-cell lymphoproliferations and the vast majority of PTCL-NOS.…”

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confidence: 99%

Disturbed expression of the T-cell receptor/CD3 complex and associated signaling molecules in CD30+ T-cell lymphoproliferations

Geissinger¹,

Sadler²,

Roth³

et al. 2010

Haematologica

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ConclusionsSeverely altered expression of the T-cell receptor/CD3 complex, T-cell receptor-associated transcription factors and signal transduction molecules is a common characteristic of systemic and cutaneous CD30 + lymphoproliferations, although the clinical behavior of these entities is very different. Since peripheral T-cell lymphomas, not otherwise specified retain the full expression program required for functioning T-cell receptor signaling, the differential expression of a subset of these markers might be of diagnostic utility in distinguishing peripheral T-cell lymphomas, not otherwise specified from the entire group of CD30 + lymphoproliferations.Key words: systemic and cutaneous CD30 + lymphoproliferations, anaplastic large cell lymphoma, lymphomatoid papulosis, ALCL, LyP, TCR.Citation: Geissinger E, Sadler P, Roth S, Grieb T, Puppe B, Müller N, Reimer P, Vetter-Kauczok CS, Wenzel J, Bonzheim I, Rüdiger T, Müller-Hermelink HK, and Rosenwald A. Disturbed expression of the T-cell receptor/CD3 complex and associated signaling molecules in CD30+ T-cell lymphoproliferations. Haematologica 20010;95(10):1697-1704. doi:10.3324/haematol.2009 This is an open-access paper. Disturbed expression of the T-cell receptor/CD3 complex and associated signaling molecules in CD30 + T-cell lymphoproliferations © F e r r a t a S t o r t i F o u n d a t i o nIntroduction CD30 + T-cell lymphoproliferations comprise a spectrum of clinically heterogeneous entities, including systemic anaplastic large cell lymphomas (ALCL) as well as primary cutaneous CD30 + T-cell lymphoproliferative disorders. Morphologically, these entities are characterized by the proliferation of highly atypical, anaplastic CD30 + T cells. Despite the frequent detection of clonally rearranged Tcell receptor (TCR) genes, the expression of T-cell-specific antigens in the tumor cells is not consistently detectable. 1 Systemic ALCL comprise approximately 15% of all peripheral T-cell lymphomas (PTCL) in Europe 2 and are divided into anaplastic lymphoma kinase (ALK) positive and negative subgroups (ALK + and ALK -systemic ALCL), whereas primary cutaneous CD30 + T-cell lymphoproliferative disorders represent a spectrum of skin lesions with diverging and in part overlapping clinical and morphological features. CD30 + T-cell lymphoproliferative disorders include primary cutaneous ALCL, lymphomatoid papulosis and so-called borderline lesions, [3][4][5] but even with the knowledge of the clinical presentation and a detailed morphological and immunohistochemical picture it is sometimes difficult, if not impossible, to classify a particular cutaneous lesion correctly.While the transforming properties of ALK over-expression have been clearly demonstrated ,6,7 the transformation mechanisms in ALK -systemic ALCL and primary cutaneous CD30 + T-cell lymphoproliferative disorders are poorly understood. CD30 itself, a cytokine receptor belonging to the tumor necrosis factor receptor superfamily, has been a research focus over the past years, but whether CD30 signaling lea...

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The structure, regulation, and function of ZAP‐70

Cited by 184 publications

References 76 publications

HIV-1 Nef Limits Communication between Linker of Activated T Cells and SLP-76 To Reduce Formation of SLP-76–Signaling Microclusters following TCR Stimulation

HIV-1 Nef Limits Communication between Linker of Activated T Cells and SLP-76 To Reduce Formation of SLP-76–Signaling Microclusters following TCR Stimulation

Tyrosines in the Carboxyl Terminus Regulate Syk Kinase Activity and Function

Disturbed expression of the T-cell receptor/CD3 complex and associated signaling molecules in CD30+ T-cell lymphoproliferations

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