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Autor     Jennifer E. Smith-Garvin, Gary A. Koretzky, and Martha S. Jordan
Titel    T Cell Activation
Zeitschrift    Annual Review of Immunology
Ausgabe    27
Jahr    2009
Seiten    591–619
DOI    10.1146/annurev.immunol.021908.132706.
URL    http://www.annualreviews.org/doi/abs/10.1146/annurev.immunol.021908.132706, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2740335/ (Author Manuscript)

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Fußnoten    yes
Fragmente    1


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[1.] Analyse:Asa/Fragment 018 02 - Diskussion
Zuletzt bearbeitet: 2014-08-14 00:15:09 Graf Isolan
Asa, Fragment, SMWFragment, Schutzlevel, Smith-Garvin et al 2009, Verschleierung, ZuSichten

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Seite: 18, Zeilen: 2ff (complete page)
Quelle: Smith-Garvin et al 2009
Seite(n): 3-4, 5, Zeilen: 3:24-32.47-48 - 4:1-3; 5:42-43.48-49 - 6:1-11
1.1.1.3 The CD3 complex

The TcR is a complex consisting of the variable αβ chains noncovalently associated with the nonpolymorphic CD3 proteins. The CD3 proteins exist as a series of dimers including γε, δε, and ζζ associated with a single αβ heterodimer. These subunits lack enzymatic activity, but transduce signals via their immunoreceptor tyrosine-based activation motifs (ITAMs) (Reth, 1989). Tyrosine phosphorylation of the ITAMs serves as docking sites for interactions with other proteins. The earliest step in intracellular signaling following TcR ligation is the activation of src-family kinases p56lck and p59Fyn protein tyrosine kinases (PTKs), leading to phosphorylation of the CD3 ITAMs, followed by recruitment of Syk kinase family member ZAP-70 (ζ-associated phosphoprotein of 70 kDa) (Fig.3).

The phosphorylated CD3ζ is a recruitment site of the ZAP-70 PTK (Chan et al., 1992). The engagement of the TcR leads to Src family PTK activity resulting in ITAM phosphorylation and recruitment of ZAP-70. This converted the TcR: CD3 with no intrinsic enzymatic function into an active PTK associated molecular complex able to phosphorylate a spectrum of substrates leading to a myriad of downstream signals that, when integrated appropriately along with signals from other co-receptors, lead to T cell activation (Iwashima et al., 1994).

ZAP-70 targets are the transmembrane adapter protein linker for the activation of T cells (LAT) and the cytosolic adapter protein Src homology2 (SH2) domain-containing leukocyte phosphoprotein of 76 kDa (SLP-76) (Bubeck Wardenburg et al., 1996; Zhang et al., 1998). These two adapters form the backbone of the complex that organizes effector molecules in a way that allows the activation of multiple signaling pathways. The loss of either LAT or SLP-76 results in a nearly complete loss of TcR signal transduction reminiscent of Syk/ZAP-70 or Lck/Fyn double-deficient T cells (Koretzky et al., 2006; Sommers et al., 2004; Zhang et al., 1999). LAT contains nine tyrosines that are phosphorylated upon TcR engagement, which bind the C-terminal SH2 domain of PLCγ1, the p85 subunit of phosphoinositide 3-kinase (PI3K), and the adapters growth factor receptor-bound protein 2 (GRB2) and GRB2-related adapter downstream of Shc (Gads) (Sommers et al., 2004). SLP-76 is then recruited to phosphorylated LAT via their mutual binding partner Gads (Liu et al., 1999).


Bubeck Wardenburg, J., Fu, C., Jackman, J.K., Flotow, H., Wilkinson, S.E., Williams, D.H., Johnson, R., Kong, G., Chan, A.C., and Findell, P.R. (1996). Phosphorylation of SLP-76 by the ZAP-70 protein-tyrosine kinase is required for T-cell receptor function. J Biol Chem 271, 19641-19644.

Iwashima, M., Irving, B.A., van Oers, N.S., Chan, A.C., and Weiss, A. (1994). Sequential interactions of the TCR with two distinct cytoplasmic tyrosine kinases. Science 263, 1136-1139.

Koretzky, G.A., Abtahian, F., and Silverman, M.A. (2006). SLP76 and SLP65: complex regulation of signalling in lymphocytes and beyond. Nat Rev Immunol 6, 67-78.

Liu, S.K., Fang, N., Koretzky, G.A., and McGlade, C.J. (1999). The hematopoietic-specific adaptor protein gads functions in T-cell signaling via interactions with the SLP-76 and LAT adaptors. Curr Biol 9, 67-75.

Reth, M. (1989). Antigen receptor tail clue. Nature 338, 383-384.

Sommers, C.L., Samelson, L.E., and Love, P.E. (2004). LAT: a T lymphocyte adapter protein that couples the antigen receptor to downstream signaling pathways. Bioessays 26, 61-67.

Zhang, W., Sloan-Lancaster, J., Kitchen, J., Trible, R.P., and Samelson, L.E. (1998). LAT: the ZAP-70 tyrosine kinase substrate that links T cell receptor to cellular activation. Cell 92, 83-92.

Zhang, W., Sloan-Lancaster, J., Kitchen, J., Trible, R.P., and Samelson, L.E. (1998). LAT: the ZAP-70 tyrosine kinase substrate that links T cell receptor to cellular activation. Cell 92, 83-92.

[Page 3]

It was speculated, therefore, that tyrosine phosphorylation of the ITAMs might serve as docking sites for interactions with other proteins. Indeed, it was soon shown that phosphorylated CD3ζ (and later other ITAM-containing proteins) was a recruitment site of a 70 kDa phosphoprotein that turned out to be the syk kinase family member ZAP-70 (ζ-associated protein of 70 kDa) PTK (25). A model therefore emerged that engagement of the TCR led to src PTK activity resulting in ITAM phosphorylation and recruitment of ZAP-70. This converted the TCR with no intrinsic enzymatic function to an active PTK able to phosphorylate a spectrum of substrates leading to a myriad of downstream signals that, when integrated appropriately (along with signals from other co-receptors), leads to T cell activation (26).

[...]

Since identification of the TCR as a complex consisting of the variable αβ chains noncovalently associated with the non-polymorphic CD3 proteins, considerable work has gone

[Page 4]

It is now known that the CD3 proteins exist as a series of dimers including γε, δε, and ζζ associated with a single αβ heterodimer.

[Page 5]

The earliest step in intracellular signaling following TCR ligation is the activation of src (lck and fyn) PTKs leading to phosphorylation of the CD3 ITAMs. [...]

Among the most important of the ZAP-70 targets are the transmembrane adapter protein linker for the activation of T cells (LAT) and the cytosolic adapter protein src homology 2 (SH2)

[Page 6]

domain-containing leukocyte phosphoprotein of 76 kDa (SLP-76) (42,43). These two adapters form the backbone of the complex that organizes effector molecules in the correct spatiotemporal manner to allow for the activation of multiple signaling pathways. The importance of these adapters is underscored by studies showing that the loss of either LAT or SLP-76 results in a near complete loss of TCR signal transduction reminiscent of syk/ZAP-70 or lck/fyn doubly deficient T cells (44–46).

LAT contains nine tyrosines that are phosphorylated upon TCR engagement, which have been shown to bind the C-terminal SH2 domain of PLCγ1, the p85 subunit of phosphoinositide 3-kinase (PI3K), and the adapters growth factor receptor-bound protein 2 (GRB2) and GRB2- related adapter downstream of Shc (Gads) (reviewed in 45). SLP-76 is then recruited to phosphorylated LAT via their mutual binding partner Gads (47).



21. Reth M. Antigen receptor tail clue. Nature 1989;338:383–4. [PubMed: 2927501]

25. Chan AC, Iwashima M, Turck CW, Weiss A. ZAP-70: a 70 kd protein-tyrosine kinase that associates with the TCR zeta chain. Cell 1992;71:649–62. [PubMed: 1423621] Describes the cloning and initial characterization of ZAP-70, the syk family PTK essential for coupling the TCR to its downstream signaling machinery.

26. Iwashima M, Irving BA, van Oers NS, Chan AC, Weiss A. Sequential interactions of the TCR with two distinct cytoplasmic tyrosine kinases. Science 1994;263:1136–9. [PubMed: 7509083]

42. Zhang W, Sloan-Lancaster J, Kitchen J, Trible RP, Samelson LE. LAT: the ZAP-70 tyrosine kinase substrate that links T cell receptor to cellular activation. Cell 1998;92:83–92. [PubMed: 9489702]

43. Bubeck Wardenburg J, Fu C, Jackman JK, Flotow H, Wilkinson SE, Williams DH, Johnson R, Kong G, Chan AC, Findell PR. Phosphorylation of SLP-76 by the ZAP-70 protein-tyrosine kinase is required for T-cell receptor function. J Biol Chem 1996;271:19641–4. [PubMed: 8702662]

44. Koretzky GA, Abtahian F, Silverman MA. SLP76 and SLP65: complex regulation of signalling in lymphocytes and beyond. Nat Rev Immunol 2006;6:67–78. [PubMed: 16493428]

45. Sommers CL, Samelson LE, Love PE. LAT: a T lymphocyte adapter protein that couples the antigen receptor to downstream signaling pathways. Bioessays 2004;26:61–7. [PubMed: 14696041]

46. Zhang W, Sommers CL, Burshtyn DN, Stebbins CC, DeJarnette JB, Trible RP, Grinberg A, Tsay HC, Jacobs HM, Kessler CM, Long EO, Love PE, Samelson LE. Essential role of LAT in T cell development. Immunity 1999;10:323–32. [PubMed: 10204488]

47. Liu SK, Fang N, Koretzky GA, McGlade CJ. The hematopoietic-specific adaptor protein gads functions in T-cell signaling via interactions with the SLP-76 and LAT adaptors. Curr Biol 1999;9:67–75. [PubMed: 10021361] LAT−/− mice reveal a complete block in T cell development that, along with studies describing SLP-76−/− mice, exemplifies in vivo the essential role of adapter proteins for signal transduction.

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