The Linker for activation of T cells, also known as linker of activated T cells or LAT, is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
involved in the
T-cell antigen receptor signal transduction pathway which in humans is encoded by the ''LAT''
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
.
Alternative splicing
Alternative splicing, or alternative RNA splicing, or differential splicing, is an alternative splicing process during gene expression that allows a single gene to code for multiple proteins. In this process, particular exons of a gene may be i ...
results in multiple transcript variants encoding different isoforms.
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
MHC Class II molecules are a class of major histocompatibility complex (MHC) molecules normally found only on professional antigen-presenting cells such as dendritic cells, mononuclear phagocytes, some endothelial cells, thymic epithelial cell ...
. LAT is a transmembrane protein localizes to
lipid raft
The plasma membranes of cells contain combinations of glycosphingolipids, cholesterol and protein receptors organised in glycolipoprotein lipid microdomains termed lipid rafts. Their existence in cellular membranes remains somewhat controversial ...
s (also known as
glycosphingolipid
Glycosphingolipids are a subtype of glycolipids containing the amino alcohol sphingosine. They may be considered as sphingolipids with an attached carbohydrate. Glycosphingolipids are a group of lipids (more specifically, sphingolipids) and are a ...
-enriched microdomains or GEMs) and acts as a docking site for
SH2 domain
The SH2 (Src Homology 2) domain is a structurally conserved protein domain contained within the Src oncoprotein and in many other intracellular signal-transducing proteins. SH2 domains allow proteins containing those domains to dock to phosphor ...
-containing proteins.
Upon
phosphorylation
In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...
, 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
ZAP-70 (Zeta-chain-associated protein kinase 70) is a protein normally expressed near the surface membrane of lymphocytes (T cells, natural killer cells, and a subset of B cells). It is most prominently known to be recruited upon antigen binding t ...
, a Syk family protein
tyrosine kinase
A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell. It functions as an "on" or "off" switch in many cellular functions.
Tyrosine kinases belong to a larger cla ...
, to bind, become activated, and phosphorylate LAT.
ZAP-70
ZAP-70 (Zeta-chain-associated protein kinase 70) is a protein normally expressed near the surface membrane of lymphocytes (T cells, natural killer cells, and a subset of B cells). It is most prominently known to be recruited upon antigen binding t ...
phosphorylates tyrosines on LAT, specifically tyrosines 171, 191, and 226 is able to interact with adaptor proteins that have a
SH2 domain
The SH2 (Src Homology 2) domain is a structurally conserved protein domain contained within the Src oncoprotein and in many other intracellular signal-transducing proteins. SH2 domains allow proteins containing those domains to dock to phosphor ...
, 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
Lymphocyte cytosolic protein 2 (SH2 domain containing leukocyte protein of 76kDa), also known as LCP2 or SLP-76, is a signal-transducing adaptor protein expressed in T cells and myeloid cells and is important in the signaling of T-cell recepto ...
, 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
Lymphocyte cytosolic protein 2 (SH2 domain containing leukocyte protein of 76kDa), also known as LCP2 or SLP-76, is a signal-transducing adaptor protein expressed in T cells and myeloid cells and is important in the signaling of T-cell recepto ...
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
A phosphoprotein is a protein that is posttranslationally modified by the attachment of either a single phosphate group, or a complex molecule such as 5'-phospho-DNA, through a phosphate group. The target amino acid is most often serine, threonin ...
of 36–38
kDa
The dalton or unified atomic mass unit (symbols: Da or u) is a non-SI unit of mass widely used in physics and chemistry. It is defined as of the mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state and at re ...
(pp. 36–38) rapidly
phosphorylated
In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...
on
tyrosine
-Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a non-essential amino acid with a polar side group. The word "tyrosine" is from the Gr ...
residues following
TCR ligation.
Cloning of the
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
revealed that the
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
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
Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...
with:
*
GRAP2
GRB2-related adapter protein 2 also known as GRB2-related adaptor downstream of Shc (GADS) is a 37 kDa protein that in humans is encoded by the ''GRAP2'' gene.
Function
This gene encodes a member of the GRB2/Sem5/Drk family. This member is an ...
,
*
GRAP
GRB2-related adapter protein is a protein that in humans is encoded by the ''GRAP'' gene.
This gene encodes a member of the GRB2/Sem5 ('' C. elegans'' homolog)/Drk (''Drosophila'' homolog) family. This member functions as a cytoplasmic signalin ...
,
[
* Grb2,][
* ]ITK
Itk is a framework for building mega-widgets using the Incr Tcl
incr Tcl (commonly stylised as '' ncr Tcl/nowiki>'', and often abbreviated to ''itcl'') is a set of object-oriented extensions for the Tcl programming language. It is widely us ...
,
* MAP4K1
Mitogen-activated protein kinase kinase kinase kinase 1 is a protein kinase that in humans is encoded by the ''MAP4K1'' gene. It is also known as HPK1 (Hematopoietic Progenitor Kinase 1). The protein has been shown to play a role in JNK activatio ...
* PIK3R1
Phosphatidylinositol 3-kinase regulatory subunit alpha is an enzyme that in humans is encoded by the ''PIK3R1'' gene.
Function
Phosphatidylinositol 3-kinase phosphorylates the inositol ring of phosphatidylinositol at the 3-prime position. The e ...
,[
* ]PLCG1
Phospholipase C, gamma 1, also known as PLCG1,is a protein that in humans involved in cell growth, migration, apoptosis, and proliferation. It is encoded by the ''PLCG1'' gene and is part of the PLC superfamily.
Function
PLCγ1 is a cell grow ...
,
* SHB,
* VAV1
Proto-oncogene vav is a protein that in humans is encoded by the ''VAV1'' gene.
Function
The protein encoded by this proto-oncogene is a member of the Dbl family of guanine nucleotide exchange factors (GEF) for the Rho family of GTP binding ...
,[ and
* ]ZAP-70
ZAP-70 (Zeta-chain-associated protein kinase 70) is a protein normally expressed near the surface membrane of lymphocytes (T cells, natural killer cells, and a subset of B cells). It is most prominently known to be recruited upon antigen binding t ...
.[
]
References
Further reading
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{{DEFAULTSORT:Linker Of Activated T Cells
Transmembrane proteins