Linker for activation of T cells

Function

The LAT protein encoded by the gene of the same name, plays a key role in the diversification of T cell signaling pathways following activation of the T-cell antigen receptor (TCR) signal transduction pathway, which is first catalyzed by TCR binding to MHC class II. LAT is a transmembrane protein localizes to lipid rafts (also known as glycosphingolipid-enriched microdomains or GEMs) and acts as a docking site for SH2 domain-containing proteins. Upon phosphorylation, this protein recruits multiple adaptor proteins and downstream signaling molecules into multimolecular signaling complexes located near the site of TCR engagement. In mouse thymocytes, lack of functional LAT or the inability for LAT to be phosphorylated leads to complete lack of T cell development. Moreover, mutation and deletion of LAT hampers overall TCR mediated T cell response.

Signaling Pathway

Prior to phosphorylation of LAT, the TCR signal transduction pathway is initiated by a TCR interacting with peptide bound MHC, and immediately leads to the activation of LCK and Fyn, which are members of the Src family of kinases. Activated LCK subsequently phosphorylates the immunoreceptor tyrosine-based activation motifs (ITAMs) of the T-cell surface glycoprotein CD3 zeta chain, which is a protein associated with the TCR complex, in two specific locations. The phosphorylated ITAMs of the CD3 zeta chain allows for ZAP-70, a Syk family protein tyrosine kinase, to bind, become activated, and phosphorylate LAT.

ZAP-70 phosphorylates tyrosines on LAT, specifically tyrosines 171, 191, and 226 is able to interact with adaptor proteins that have a SH2 domain, and are members of the Grb2 protein family, such as Gads. Moreover, phosphorylation of LAT tyrosine 132 allows for  PLCγ1-LAT association, which, when combined with concurrent Gads binding to tyrosines 171 or 191 of LAT, allows for the formation of a LAT-nucleated signaling complex. LAT-interacting Gads attracts the binding of SLP-76, which recruits additional effector molecules that assist in the stabilization of PLCγ1 binding to the LAT complex. The resulting LAT signaling complex, which contains the molecules  PLCγ1, Grb2, Gads, SLP-76 and the necessary associated ligands thus allow for diversification of the TCR signaling pathway through actin production, the activation of transcription factors, and other messaging signals.

Discovery

LAT was described in the early 1990s as a phosphoprotein of 36–38 kDa (pp. 36–38) rapidly phosphorylated on tyrosine residues following TCR ligation. Cloning of the gene revealed that the protein product is a type III (leaderless) transmembrane protein of 262 aminoacids (long form) or 233 aminoacids (short form) in humans, 242 aminoacids in mouse, and 241 aminoacids in rat.

Interactions

The Linker for Activation of T cells has been shown to interact with:

• GRAP2,
• GRAP,
• Grb2,
• ITK,
• MAP4K1
• PIK3R1,
• PLCG1,
• SHB,
• VAV1, and
• ZAP-70.

References

References

1. (January 1998). "LAT: the ZAP-70 tyrosine kinase substrate that links T cell receptor to cellular activation". Cell.
2. "Entrez Gene: LAT Linker of Activated T cells".
3. (March 2004). "Transmembrane adaptor proteins in membrane microdomains: important regulators of immunoreceptor signaling". Immunology Letters.
4. (October 2015). "The linker for activation of T cells (LAT) signaling hub: from signaling complexes to microclusters". The Journal of Biological Chemistry.
5. (2021-04-16). "Adapting T Cell Receptor Ligand Discrimination Capability ''via'' LAT". Frontiers in Immunology.
6. (December 2021). "T cell receptor (TCR) signaling in health and disease". Signal Transduction and Targeted Therapy.
7. (2013). "The adaptor protein LAT serves as an integration node for signaling pathways that drive T cell activation". Wiley Interdisciplinary Reviews. Systems Biology and Medicine.
8. (July 1994). "GRB2 and phospholipase C-gamma 1 associate with a 36- to 38-kilodalton phosphotyrosine protein after T-cell receptor stimulation". Molecular and Cellular Biology.
9. (April 1998). "Molecular cloning of the cDNA encoding pp36, a tyrosine-phosphorylated adaptor protein selectively expressed by T cells and natural killer cells". The Journal of Experimental Medicine.
10. (January 1999). "The hematopoietic-specific adaptor protein gads functions in T-cell signaling via interactions with the SLP-76 and LAT adaptors". Current Biology.
11. (May 1999). "Grf40, A novel Grb2 family member, is involved in T cell signaling through interaction with SLP-76 and LAT". The Journal of Experimental Medicine.
12. (October 1999). "Itk/Emt/Tsk activation in response to CD3 cross-linking in Jurkat T cells requires ZAP-70 and Lat and is independent of membrane recruitment". The Journal of Biological Chemistry.
13. (June 2001). "Involvement of hematopoietic progenitor kinase 1 in T cell receptor signaling". The Journal of Biological Chemistry.
14. (June 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". The Biochemical Journal.
15. (August 1998). "LAT palmitoylation: its essential role in membrane microdomain targeting and tyrosine phosphorylation during T cell activation". Immunity.
16. (September 1999). "Requirement of the Src homology 2 domain protein Shb for T cell receptor-dependent activation of the interleukin-2 gene nuclear factor for activation of T cells element in Jurkat T cells". The Journal of Biological Chemistry.
17. (July 2002). "Shb links SLP-76 and Vav with the CD3 complex in Jurkat T cells". European Journal of Biochemistry.
18. (August 2002). "Phosphorylation of the linker for activation of T-cells by Itk promotes recruitment of Vav". Biochemistry.