Lck
Encyclopedia
Lck is a protein
that is found inside specialized cells
of the immune system
called lymphocytes. Lck is a tyrosine kinase
, which phosphorylates tyrosine
residues of certain protein
s involved in the intracellular
signaling pathways of these lymphocytes. It is a member of the Src
family of tyrosine kinases.
s. It associates with the cytoplasm
ic tails of the CD4
and CD8
co-receptors on T helper cells and cytotoxic T cells, respectively, to assist signaling from the T cell receptor
(TCR) complex. When the T cell receptor
is engaged by the specific antigen
presented by MHC
, Lck acts to phosphorylate the intracellular chains of the CD3
and ζ-chains of the TCR complex, allowing another cytoplasm
ic tyrosine
kinase
called ZAP-70
to bind to them. Lck then phosphorylates and activates ZAP-70, which in turn phosphorylates another molecule in the signaling cascade called LAT
(short for Linker of Activated T cells), a transmembrane protein
that serves as a docking site for a number of other proteins, the most important of which are Shc
-Grb2
-SOS, PI3K, and phospholipase C
(PLC).
The tyrosine phosphorylation cascade
initiated by Lck culminates in the intracellular mobilization of a calcium
(Ca2+) ion
s and activation of important signaling cascades within the lymphocyte. These include the Ras
-MEK
-ERK
pathway, which goes on to activate certain transcription factor
s such as NFAT
, NF-κB, and AP-1
. These transcription factors regulate the production of a plethora of gene products, most notable, cytokine
s such as Interleukin-2 that promote long-term proliferation and differentiation of the activated lymphocytes.
The function of Lck has been studied using several biochemical methods, including gene knockout
(knock-out mice), Jurkat cells deficient in Lck (JCaM1.6), and siRNA
-mediated RNA interference.
and palmitoylated
, which tethers the protein to the plasma membrane of the cell. The protein furthermore contains a SH3 domain
, a SH2 domain
and in the C-terminal part the tyrosine kinase
domain. The two main phosphorylation sites on Lck are tyrosines 394 and 505. The former is an autophosphorylation site and is linked to activation of the protein. The latter is phosphorylated by Csk
, which inhibits Lck because the protein folds up and binds its own SH2 domain. Lck thus serves as an instructive example that protein phosphorylation may result in both activation and inhibition.
, ZAP-70
, SLP-76, the IL-2 receptor, Protein kinase C
, ITK
, PLC
, SHC
, RasGAP, Cbl, Vav1
, and PI3K.
-mediated pathway.
with PTPN6
, ZAP-70
, Syk
, P110α, ADAM15
, CD4
, CD44
, PTPRC, DLG1
, CD2
, Protein unc-119 homolog
, UBE3A
, NOTCH1
and COUP-TFII
.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that is found inside specialized cells
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
of the immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
called lymphocytes. Lck is a tyrosine kinase
Tyrosine kinase
A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a protein in a cell. It functions as an "on" or "off" switch in many cellular functions....
, which phosphorylates tyrosine
Tyrosine
Tyrosine or 4-hydroxyphenylalanine, is one of the 22 amino acids that are used by cells to synthesize proteins. Its codons are UAC and UAU. It is a non-essential amino acid with a polar side group...
residues of certain protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s involved in the intracellular
Intracellular
Not to be confused with intercellular, meaning "between cells".In cell biology, molecular biology and related fields, the word intracellular means "inside the cell".It is used in contrast to extracellular...
signaling pathways of these lymphocytes. It is a member of the Src
Src family kinase
Src family kinase is a family of non-receptor tyrosine kinases that includes nine members: Src, Yes, Fyn, and Fgr, forming the SrcA subfamily, Lck, Hck, Blk, and Lyn in the SrcB subfamily, and Frk in its own subfamily...
family of tyrosine kinases.
Lck and T cell signaling
Lck is most commonly found in T cellT cell
T cells or T lymphocytes belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity. They can be distinguished from other lymphocytes, such as B cells and natural killer cells , by the presence of a T cell receptor on the cell surface. They are...
s. It associates with the cytoplasm
Cytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...
ic tails of the CD4
CD4
CD4 is a glycoprotein expressed on the surface of T helper cells, monocytes, macrophages, and dendritic cells. It was discovered in the late 1970s and was originally known as leu-3 and T4 before being named CD4 in 1984...
and CD8
CD8
CD8 is a transmembrane glycoprotein that serves as a co-receptor for the T cell receptor . Like the TCR, CD8 binds to a major histocompatibility complex molecule, but is specific for the class I MHC protein. There are two isoforms of the protein, alpha and beta, each encoded by a different gene...
co-receptors on T helper cells and cytotoxic T cells, respectively, to assist signaling from the T cell receptor
T cell receptor
The T cell receptor or TCR is a molecule found on the surface of T lymphocytes that is responsible for recognizing antigens bound to major histocompatibility complex molecules...
(TCR) complex. When the T cell receptor
T cell receptor
The T cell receptor or TCR is a molecule found on the surface of T lymphocytes that is responsible for recognizing antigens bound to major histocompatibility complex molecules...
is engaged by the specific antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
presented by MHC
Major histocompatibility complex
Major histocompatibility complex is a cell surface molecule encoded by a large gene family in all vertebrates. MHC molecules mediate interactions of leukocytes, also called white blood cells , which are immune cells, with other leukocytes or body cells...
, Lck acts to phosphorylate the intracellular chains of the CD3
CD3 receptor
In immunology, the CD3 T-Cell Co-Receptor is a protein complex and is composed of four distinct chains. In mammals, the complex contains a CD3γ chain, a CD3δ chain, and two CD3ε chains. These chains associate with a molecule known as the T cell receptor and the ζ-chain to generate an activation...
and ζ-chains of the TCR complex, allowing another cytoplasm
Cytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...
ic tyrosine
Tyrosine
Tyrosine or 4-hydroxyphenylalanine, is one of the 22 amino acids that are used by cells to synthesize proteins. Its codons are UAC and UAU. It is a non-essential amino acid with a polar side group...
kinase
Kinase
In chemistry and biochemistry, a kinase is a type of enzyme that transfers phosphate groups from high-energy donor molecules, such as ATP, to specific substrates, a process referred to as phosphorylation. Kinases are part of the larger family of phosphotransferases...
called ZAP-70
ZAP-70
ZAP-70 is an abbreviation for Zeta-chain-associated protein kinase 70 . The protein is a member in the protein-tyrosine kinase family...
to bind to them. Lck then phosphorylates and activates ZAP-70, which in turn phosphorylates another molecule in the signaling cascade called LAT
Linker of activated T cells
Linker of Activated T cells, also known as LAT, is a protein which in humans is encoded by the LAT gene. Alternative splicing results in multiple transcript variants encoding different isoforms.-Function:...
(short for Linker of Activated T cells), a transmembrane protein
Transmembrane protein
A transmembrane protein is a protein that goes from one side of a membrane through to the other side of the membrane. Many TPs function as gateways or "loading docks" to deny or permit the transport of specific substances across the biological membrane, to get into the cell, or out of the cell as...
that serves as a docking site for a number of other proteins, the most important of which are Shc
SH2 domain
The SH2 domain is a structurally conserved protein domain contained within the Src oncoprotein and in many other intracellular signal-transducing proteins...
-Grb2
Grb2
Growth factor receptor-bound protein 2 also known as Grb2 is an adaptor protein involved in signal transduction/cell communication. In humans, the GRB2 protein is encoded by the GRB2 gene....
-SOS, PI3K, and phospholipase C
Phospholipase C
Phosphoinositide phospholipase C is a family of eukaryotic intracellular enzymes that play an important role in signal transduction processes. In general, this enzyme is denoted as Phospholipase C, although three other families of phospholipase C enzymes have been identified in bacteria and in...
(PLC).
The tyrosine phosphorylation cascade
Biochemical cascade
A biochemical cascade is a series of chemical reactions in which the products of one reaction are consumed in the next reaction. There are several important biochemical cascade reactions in biochemistry, including the enzymatic cascades, such as the coagulation cascade and the complement system,...
initiated by Lck culminates in the intracellular mobilization of a calcium
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
(Ca2+) ion
Ion
An ion is an atom or molecule in which the total number of electrons is not equal to the total number of protons, giving it a net positive or negative electrical charge. The name was given by physicist Michael Faraday for the substances that allow a current to pass between electrodes in a...
s and activation of important signaling cascades within the lymphocyte. These include the Ras
Ras
Ras is the name given to a family of related proteins found inside cells, including human cells. All Ras protein family members belong to a class of protein called small GTPase, and are involved in transmitting signals within cells...
-MEK
Mitogen-activated protein kinase
Mitogen-activated protein kinases are serine/threonine-specific protein kinases that respond to extracellular stimuli and regulate various cellular activities, such as gene expression, mitosis, differentiation, proliferation, and cell survival/apoptosis.-Activation:MAP kinases are activated...
-ERK
Extracellular signal-regulated kinases
In molecular biology, extracellular-signal-regulated kinases or classical MAP kinases are widely expressed protein kinase intracellular signalling molecules that are involved in functions including the regulation of meiosis, mitosis, and postmitotic functions in differentiated cells...
pathway, which goes on to activate certain transcription factor
Transcription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...
s such as NFAT
NFAT
Nuclear factor of activated T-cells is a general name applied to a family of transcription factors shown to be important in immune response. One or more members of the NFAT family is expressed in most cells of the immune system...
, NF-κB, and AP-1
AP-1
AP1 or AP-1 can refer to:* AP-1 * Autopista AP-1, a Spanish motorway* Caproni AP.1, a 1934 Italian attack aircraft monoplane* USS Henderson...
. These transcription factors regulate the production of a plethora of gene products, most notable, cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
s such as Interleukin-2 that promote long-term proliferation and differentiation of the activated lymphocytes.
The function of Lck has been studied using several biochemical methods, including gene knockout
Gene knockout
A gene knockout is a genetic technique in which one of an organism's genes is made inoperative . Also known as knockout organisms or simply knockouts, they are used in learning about a gene that has been sequenced, but which has an unknown or incompletely known function...
(knock-out mice), Jurkat cells deficient in Lck (JCaM1.6), and siRNA
Sírna
Sírna Sáeglach , son of Dian mac Demal, son of Demal mac Rothechtaid, son of Rothechtaid mac Main, was, according to medieval Irish legend and historical tradition, a High King of Ireland...
-mediated RNA interference.
Lck structure
Lck is a 56-kilodalton protein. The N-terminal tail of Lck is myristoylatedMyristoylation
Myristoylation is an irreversible, co-translational protein modification found in animals, plants, fungi, protozoans and viruses. In this protein modification, a myristoyl group is covalently attached via an amide bond to the alpha-amino group of an N-terminal amino acid of a nascent polypeptide...
and palmitoylated
Palmitoylation
S-Palmitoylation is the covalent attachment of fatty acids, such as palmitic acid, to cysteine residues of membrane proteins. The precise function of palmitoylation depends on the particular protein being considered. Palmitoylation enhances the hydrophobicity of proteins and contributes to their...
, which tethers the protein to the plasma membrane of the cell. The protein furthermore contains a SH3 domain
SH3 domain
The SRC Homology 3 Domain is a small protein domain of about 60 amino acids residues first identified as a conserved sequence in the viral adaptor protein v-Crk and the non-catalytic parts of enzymes such as phospholipase and several cytoplasmic tyrosine kinases such as Abl and Src...
, a SH2 domain
SH2 domain
The SH2 domain is a structurally conserved protein domain contained within the Src oncoprotein and in many other intracellular signal-transducing proteins...
and in the C-terminal part the tyrosine kinase
Tyrosine kinase
A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a protein in a cell. It functions as an "on" or "off" switch in many cellular functions....
domain. The two main phosphorylation sites on Lck are tyrosines 394 and 505. The former is an autophosphorylation site and is linked to activation of the protein. The latter is phosphorylated by Csk
C-src tyrosine kinase
C-src tyrosine kinase, also known as CSK, is a human protein and gene. It includes an SH2 domain, an SH3 domain, and a tyrosine kinase domain. This protein specifically phosphorylates Tyr-504 residue on human leukocyte-specific protein tyrosine kinase, which acts as a negative regulatory site...
, which inhibits Lck because the protein folds up and binds its own SH2 domain. Lck thus serves as an instructive example that protein phosphorylation may result in both activation and inhibition.
Lck substrates
Lck tyrosine phosphorylates a number of proteins, the most important of which are the CD3 receptorCD3 receptor
In immunology, the CD3 T-Cell Co-Receptor is a protein complex and is composed of four distinct chains. In mammals, the complex contains a CD3γ chain, a CD3δ chain, and two CD3ε chains. These chains associate with a molecule known as the T cell receptor and the ζ-chain to generate an activation...
, ZAP-70
ZAP-70
ZAP-70 is an abbreviation for Zeta-chain-associated protein kinase 70 . The protein is a member in the protein-tyrosine kinase family...
, SLP-76, the IL-2 receptor, Protein kinase C
Protein kinase C
Protein kinase C also known as PKC is a family of enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and threonine amino acid residues on these proteins. PKC enzymes in turn are activated by signals such as increases in...
, ITK
ITK
ITK may stand for:* Inuit Tapiriit Kanatami, a Canadian organisation representing Inuit* Insight Segmentation and Registration Toolkit, an extensible open source image segmentation and registration software library...
, PLC
Phospholipase C
Phosphoinositide phospholipase C is a family of eukaryotic intracellular enzymes that play an important role in signal transduction processes. In general, this enzyme is denoted as Phospholipase C, although three other families of phospholipase C enzymes have been identified in bacteria and in...
, SHC
SHC
SHC may refer to:-Science:* Src homology 2 domain-containing, in structural biology, a structural domain in signal transduction proteins* SHC1, a human gene...
, RasGAP, Cbl, Vav1
VAV1
Proto-oncogene vav is a protein that in humans is encoded by the VAV1 gene.-Interactions:VAV1 has been shown to interact with Ku70, PLCG1, Lymphocyte cytosolic protein 2, Janus kinase 2, SIAH2, S100B, Abl gene, ARHGDIB, SHB, PIK3R1, PRKCQ, Grb2, MAPK1, Syk, Linker of activated T cells, Cbl gene and...
, and PI3K.
Lck inhibition
In resting T cells, Lck is constitutively inhibited by Csk phosphorylation on tyrosine 505. Lck is also inhibited by SHP-1 dephosphorylation on tyrosine 394. Lck can also be inhibited by Cbl ubiquitin ligase, which is part of the ubiquitinUbiquitin
Ubiquitin is a small regulatory protein that has been found in almost all tissues of eukaryotic organisms. Among other functions, it directs protein recycling.Ubiquitin can be attached to proteins and label them for destruction...
-mediated pathway.
Interactions
Lck has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with PTPN6
PTPN6
Tyrosine-protein phosphatase non-receptor type 6 is an enzyme that in humans is encoded by the PTPN6 gene.Also known as Src homology region 2 domain-containing phosphatase-1 .-Interactions:...
, ZAP-70
ZAP-70
ZAP-70 is an abbreviation for Zeta-chain-associated protein kinase 70 . The protein is a member in the protein-tyrosine kinase family...
, Syk
Syk
Spleen tyrosine kinase, also known as Syk, is an enyzme which in humans is encoded by the SYK gene.- Function :SYK, along with Zap-70, is a member of the Syk family of tyrosine kinases...
, P110α, ADAM15
ADAM15
Disintegrin and metalloproteinase domain-containing protein 15 is an enzyme that in humans is encoded by the ADAM15 gene.-Interactions:ADAM15 has been shown to interact with Grb2, HCK, SNX9, Lck and SH3GL2.-External links:...
, CD4
CD4
CD4 is a glycoprotein expressed on the surface of T helper cells, monocytes, macrophages, and dendritic cells. It was discovered in the late 1970s and was originally known as leu-3 and T4 before being named CD4 in 1984...
, CD44
CD44
The CD44 antigen is a cell-surface glycoprotein involved in cell–cell interactions, cell adhesion and migration. In humans, the CD44 antigen is encoded by the CD44 gene.- Tissue distribution and isoforms :...
, PTPRC, DLG1
DLG1
Disks large homolog 1 , also known as synapse-associated protein 97 or SAP97, is a protein that in humans is encoded by the SAP97 gene....
, CD2
CD2
CD2 is a cell adhesion molecule found on the surface of T cells and natural killer cells.It has also been called T-cell surface antigen T11/Leu-5, LFA-2, LFA-3 receptor, erythrocyte receptor and rosette receptor....
, Protein unc-119 homolog
Protein unc-119 homolog
Protein unc-119 homolog A is a protein that in humans is encoded by the UNC119 gene.-Interactions:Protein unc-119 homolog has been shown to interact with Lck, ARL3, ARL2, LYN, Interleukin 5 receptor alpha subunit, CD247, CD4 and FYN....
, UBE3A
UBE3A
Ubiquitin-protein ligase E3A also known as E6AP ubiquitin-protein ligase is an enzyme that in humans is encoded by the UBE3A gene. This enzyme is involved in targeting proteins for degradation within cells...
, NOTCH1
NOTCH1
Notch homolog 1, translocation-associated , also known as NOTCH1, is a human gene encoding a single-pass transmembrane receptor.A deficiency can be associated with bicuspid aortic valve....
and COUP-TFII
COUP-TFII
COUP-TFII , also known as NR2F2 is a protein that in humans is encoded by the NR2F2 gene...
.