Diseases

Germline mutation (meaning this defect can also be transmitted onto offspring) of the linker for activation of T cells (LAT) gene PLCγ1-binding position causes fatal lymphoproliferative disease (LPD) as studies show using mice [1]. The overactive T cells that appear in these mice have malfunctioning T-cell antigen receptor (TCR)-induced calcium release but greater mitogen-activated protein kinase (MAPK) activation. LPD concerns numerous disorders in which lymphocytes are generated in extreme amounts. They usually strike in patients who have compromised immune systems. Examples of LPDs [2]:

Allergic asthma is linked with airway inflammation and hyper-sensitivity instigated by decontrolled number of cytokines being secreted by allergen-specific T-helper (Th2) cells. LAT – a membrane-associated adaptor protein supports the control of T- cell receptor signalling [3].

One study shows that LAT reduces the amount of cytokines produced by Th2 cells. As well as this, LAT also decreases lung inflammation as well as easing lung changes in terms of disease. Therefore defective LAT proteins in patients may be another factor in the causation of asthma as recent studies show.

A mutation in the 26th amino acid sequence of the LAT protein (a cysteine residue), reduces palmitoylation (is the covalent attachment of fatty acids, such as palmitic acid, to cysteine residues of membrane proteins) and stops localization to lipid rafts. This is the same effect for when there is a mutation in the 29th amino acid of the same sequence (also a cysteine residue).

The linker molecule LAT is a significant substrate of the tyrosine kinase triggered upon TCR engagement. When LAT has been phosphorylated, it binds to Grb2, PLC-gamma1 and other signalling molecules. LAT must exist in glycolipid-enriched microdomains (GEMs) for linking TCR engagement to stimulation of the Ras signalling pathway [4], which causes intracellular levels of calcium ions to rise and therefore causes the induction of the transcription factor activated T cells. This palmitoylation of LAT mainly locates into GEMs. Although the LAT transmembrane domain is adequate for membrane localization, palmitoylation at C26 and C29 is essential for efficient separation into GEMs [5]. LAT palmitoylation is essential for its tyrosine phosphorylation.

A mutation in the 132nd amino acid of the LAT protein sequence abolishes interaction with PLCG1. TCR-mediated LAT phosphorylation is vital for the membrane recruitment of signalling complexes essential for T-cell activation [6]. There are three distal tyrosines, Tyr(171), Tyr(191), and Tyr(226). All of these tyrosines are responsible for Grb2 binding. One study showed that mutation of Tyr(132) alone stopped PLCγ1 binding [7]. This affected calcium influx and stopped Erk and NF-AT activation. Similarly, mutation of all three distal tyrosines eliminated PLCγ1 binding, implying there might be numerous binding positions for PLCγ1.

Lastly, T-Cells homozygous for loss of function mutations in LAT become unresponsive to stimulation from the TCR, and thus show impaired T cell homeostatic proliferation, resulting in eventual cell death [8].

References

[1] Miyajia. M, Kortuma R.L., Suranaa R., Lia W., Woolardb K.D., R. Simpsonb M., Samelsona L.E, and Sommersa C. L (2009) Genetic evidence for the role of Erk activation in a lymphoproliferative disease of mice; Proceedings of the National Academy of Sciences; 106(34):14502

[2] http://en.wikipedia.org/wiki/Lymphoproliferative_disorders

[3] Guo X.J., Ren L.P., Sun Y.P., Zhou M., Xu W.G (2010) Linker for activation of T cells contributes to airway inflammation in an asthmatic mouse model; Chin Med J (Engl); 123(19):2676-81.

[4] Lin J., Weiss A., Finco T.S. (1999) Localization of LAT in glycolipid-enriched microdomains is required for T cell activation; J Biol Chem; 274(41):28861-4

[5] Zhang W., Trible R.P., Samelson L.E. (1998) LAT palmitoylation: its essential role in membrane microdomain targeting and tyrosine phosphorylation during T cell activation; Immunity; 9:239-246

[6] Paz P.E., Wang S., Clarke H., Lu X., Stokoe D., Abo A. (2001) Mapping the Zap-70 phosphorylation sites on LAT (linker for activation of T cells) required for recruitment and activation of signalling proteins in T cells; Biochem. J. 356:461-471

[7] Zhang W., Trible R.P., Zhu M., Liu S.K., McGlade C.J., Samelson L.E. (2000) Association of Grb2, Gads, and phospholipase C-gamma 1 with phosphorylated LAT tyrosine residues. Effect of LAT tyrosine mutations on T cell angigen receptor-mediated signaling; J Biol Chem; 275(30):23355-61.

[8] S.Shen, M.Chuck, M.Zhu, D.Fuller, C.Yang, W.Zhang. (2010) The Importance of LAT in the Activation, Homeostasis, and Regulatory Function of T Cells. The Journal of Biological Chemistry, 285, 35393-35405.


		*Diseases associated with LAT mutations:* Germline mutation (meaning this defect can also be transmitted onto offspring) of the linker for activation of T cells (LAT) gene PLCγ1-binding position causes fatal lymphoproliferative disease (LPD) as studies show using mice [1]. The overactive T cells that appear in these mice have malfunctioning T-cell antigen receptor (TCR)-induced calcium release but greater mitogen-activated protein kinase (MAPK) activation. LPD concerns numerous disorders in which lymphocytes are generated in extreme amounts. They usually strike in patients who have compromised immune systems. Examples of LPDs [2]: Follicular lymphoma Wiskott-Aldrich syndrome Acute lymphoblastic leukaemia Lymphomas Post-transplant lymphoproliferative disorder Autoimmune lymphoproliferative syndrome (ALPS) Chronic lymphocytic leukaemia Multiple myeloma Allergic asthma is linked with airway inflammation and hyper-sensitivity instigated by decontrolled number of cytokines being secreted by allergen-specific T-helper (Th2) cells. LAT – a membrane-associated adaptor protein supports the control of T- cell receptor signalling [3]. One study shows that LAT reduces the amount of cytokines produced by Th2 cells. As well as this, LAT also decreases lung inflammation as well as easing lung changes in terms of disease. Therefore defective LAT proteins in patients may be another factor in the causation of asthma as recent studies show. *Mutations associated with LAT protein:* A mutation in the 26th amino acid sequence of the LAT protein (a cysteine residue), reduces palmitoylation (is the covalent attachment of fatty acids, such as palmitic acid, to cysteine residues of membrane proteins) and stops localization to lipid rafts. This is the same effect for when there is a mutation in the 29th amino acid of the same sequence (also a cysteine residue). The linker molecule LAT is a significant substrate of the tyrosine kinase triggered upon TCR engagement. When LAT has been phosphorylated, it binds to Grb2, PLC-gamma1 and other signalling molecules. LAT must exist in glycolipid-enriched microdomains (GEMs) for linking TCR engagement to stimulation of the Ras signalling pathway [4], which causes intracellular levels of calcium ions to rise and therefore causes the induction of the transcription factor activated T cells. This palmitoylation of LAT mainly locates into GEMs. Although the LAT transmembrane domain is adequate for membrane localization, palmitoylation at C26 and C29 is essential for efficient separation into GEMs [5]. LAT palmitoylation is essential for its tyrosine phosphorylation. A mutation in the 132nd amino acid of the LAT protein sequence abolishes interaction with PLCG1. TCR-mediated LAT phosphorylation is vital for the membrane recruitment of signalling complexes essential for T-cell activation [6]. There are three distal tyrosines, Tyr(171), Tyr(191), and Tyr(226). All of these tyrosines are responsible for Grb2 binding. One study showed that mutation of Tyr(132) alone stopped PLCγ1 binding [7]. This affected calcium influx and stopped Erk and NF-AT activation. Similarly, mutation of all three distal tyrosines eliminated PLCγ1 binding, implying there might be numerous binding positions for PLCγ1. Lastly, T-Cells homozygous for loss of function mutations in LAT become unresponsive to stimulation from the TCR, and thus show impaired T cell homeostatic proliferation, resulting in eventual cell death [8]. References [1] Miyajia. M, Kortuma R.L., Suranaa R., Lia W., Woolardb K.D., R. Simpsonb M., Samelsona L.E, and Sommersa C. L (2009) Genetic evidence for the role of Erk activation in a lymphoproliferative disease of mice; Proceedings of the National Academy of Sciences; 106(34):14502 [2] http://en.wikipedia.org/wiki/Lymphoproliferative_disorders [3] Guo X.J., Ren L.P., Sun Y.P., Zhou M., Xu W.G (2010) Linker for activation of T cells contributes to airway inflammation in an asthmatic mouse model; Chin Med J (Engl); 123(19):2676-81. [4] Lin J., Weiss A., Finco T.S. (1999) Localization of LAT in glycolipid-enriched microdomains is required for T cell activation; J Biol Chem; 274(41):28861-4 [5] Zhang W., Trible R.P., Samelson L.E. (1998) LAT palmitoylation: its essential role in membrane microdomain targeting and tyrosine phosphorylation during T cell activation; Immunity; 9:239-246 [6] Paz P.E., Wang S., Clarke H., Lu X., Stokoe D., Abo A. (2001) Mapping the Zap-70 phosphorylation sites on LAT (linker for activation of T cells) required for recruitment and activation of signalling proteins in T cells; Biochem. J. 356:461-471 [7] Zhang W., Trible R.P., Zhu M., Liu S.K., McGlade C.J., Samelson L.E. (2000) Association of Grb2, Gads, and phospholipase C-gamma 1 with phosphorylated LAT tyrosine residues. Effect of LAT tyrosine mutations on T cell angigen receptor-mediated signaling; J Biol Chem; 275(30):23355-61. [8] S.Shen, M.Chuck, M.Zhu, D.Fuller, C.Yang, W.Zhang. (2010) The Importance of LAT in the Activation, Homeostasis, and Regulatory Function of T Cells. The Journal of Biological Chemistry, 285, 35393-35405.