Lck

LCK proto-oncogene, Src family tyrosine kinase
The SH2 domain of human Lck colored from blue (N-terminus) to red (C-terminus).
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1BHF​, 1BHH​, 1CWD​, 1CWE​, 1FBZ​, 1H92​, 1IJR​, 1KIK​, 1LCJ​, 1LCK​, 1LKK​, 1LKL​, 1Q68​, 1Q69​, 1QPC​, 1QPD​, 1QPE​, 1QPJ​, 1X27​, 2IIM​, 2OF2​, 2OF4​, 2OFU​, 2OFV​, 2OG8​, 2PL0​, 2ZM1​, 2ZM4​, 2ZYB​, 3AC1​, 3AC2​, 3AC3​, 3AC4​, 3AC5​, 3AC8​, 3ACJ​, 3ACK​, 3AD4​, 3AD5​, 3AD6​, 3B2W​, 3BRH​, 3BYM​, 3BYO​, 3BYS​, 3BYU​, 3KMM​, 3KXZ​, 3LCK​, 3MPM​, 4C3F​, 4D8K​
Identifiers
Symbols	LCK ; IMD22; LSK; YT16; p56lck; pp58lck
External IDs	OMIM: 153390 MGI: 96756 HomoloGene: 3911 ChEMBL: 258 GeneCards: LCK Gene
EC number	2.7.10.2
Gene ontology Molecular function • glycoprotein binding • antigen binding • protein tyrosine kinase activity • non-membrane spanning protein tyrosine kinase activity • protein serine/threonine phosphatase activity • protein binding • ATP binding • protein C-terminus binding • protein kinase binding • protein phosphatase binding • protein complex binding • SH2 domain binding • CD4 receptor binding • CD8 receptor binding • identical protein binding • phosphatidylinositol 3-kinase binding • ATPase binding Cellular component • pericentriolar material • immunological synapse • cytosol • plasma membrane • cell-cell junction • endocytic vesicle • extrinsic component of cytoplasmic side of plasma membrane • membrane raft • extracellular exosome Biological process • protein phosphorylation • cellular zinc ion homeostasis • activation of cysteine-type endopeptidase activity involved in apoptotic process • transmembrane receptor protein tyrosine kinase signaling pathway • epidermal growth factor receptor signaling pathway • aging • blood coagulation • fibroblast growth factor receptor signaling pathway • response to mechanical stimulus • response to zinc ion • positive regulation of gene expression • viral process • dephosphorylation • hemopoiesis • platelet activation • T cell differentiation • T cell costimulation • peptidyl-tyrosine autophosphorylation • Fc-epsilon receptor signaling pathway • regulation of cell proliferation • response to drug • positive regulation of tyrosine phosphorylation of Stat5 protein • response to hydrogen peroxide • innate immune response • positive regulation of gamma-delta T cell differentiation • neurotrophin TRK receptor signaling pathway • phosphatidylinositol-mediated signaling • regulation of defense response to virus by virus • T cell receptor signaling pathway • B cell receptor signaling pathway • positive regulation of T cell receptor signaling pathway • positive regulation of T cell activation • leukocyte migration • release of sequestered calcium ion into cytosol • regulation of lymphocyte activation • positive regulation of uterine smooth muscle contraction • cellular response to peptide hormone stimulus • positive regulation of intrinsic apoptotic signaling pathway Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	3932	16818
Ensembl	ENSG00000182866	ENSMUSG00000000409
UniProt	P06239	P06240
RefSeq (mRNA)	NM_001042771	NM_001162432
RefSeq (protein)	NP_001036236	NP_001155904
Location (UCSC)	Chr 1: 32.25 – 32.29 Mb	Chr 4: 129.55 – 129.57 Mb
PubMed search

Lck (or lymphocyte-specific protein tyrosine kinase) is a 56 kDa protein that is found inside specialized cells of the immune system called lymphocytes. Lck is a tyrosine kinase, which phosphorylates tyrosine residues of certain proteins involved in the intracellular signaling pathways of these lymphocytes. It is a member of the Src family of tyrosine kinases.

T cell signaling

Lck is most commonly found in T cells. It associates with the cytoplasmic tails of the CD4 and CD8 co-receptors on T helper cells and cytotoxic T cells,^[1][2] 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 cytoplasmic 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). Additionally, upon T cell activation, a fraction of kinase active Lck, translocates from outside of lipid rafts (LR) to inside lipid rafts where it interacts with and activates LR-resident Fyn, which is involved in further downstream signaling activation.^[3][4]

The tyrosine phosphorylation cascade initiated by Lck and Fyn culminates in the intracellular mobilization of calcium (Ca²⁺) ions and activation of important signaling cascades within the lymphocyte. These include the Ras-MEK-ERK pathway, which goes on to activate certain transcription factors such as NFAT, NF-κB, and AP-1. These transcription factors regulate the production of a plethora of gene products, most notable, cytokines 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.

Structure

Lck is a 56-kilodalton protein. The N-terminal tail of Lck is myristoylated 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.

Substrates

Lck tyrosine phosphorylates a number of proteins, the most important of which are the CD3 receptor, CEACAM1, ZAP-70, SLP-76, the IL-2 receptor, Protein kinase C, ITK, PLC, SHC, RasGAP, Cbl, Vav1, and PI3K.

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 ubiquitin-mediated pathway.^[5]

Interactions

Lck has been shown to interact with:

See also

• Tyrosine kinase
• T cell

References

Further reading

External links

• lck Kinase at the US National Library of Medicine Medical Subject Headings (MeSH)

PDB gallery 1bhf: P56LCK SH2 DOMAIN INHIBITOR COMPLEX  1bhh: FREE P56LCK SH2 DOMAIN  1cwd: HUMAN P56LCK TYROSINE KINASE COMPLEXED WITH PHOSPHONOPEPTIDE  1cwe: HUMAN P56LCK TYROSINE KINASE COMPLEXED WITH PHOSPHONOPEPTIDE  1fbz: Structure-based design of a novel, osteoclast-selective, nonpeptide Src SH2 inhibitor with in vivo anti-resorptive activity  1h92: SH3 DOMAIN OF HUMAN LCK TYROSINE KINASE  1ijr: Crystal structure of LCK SH2 complexed with nonpeptide phosphotyrosine mimetic  1kik: SH3 Domain of Lymphocyte Specific Kinase (LCK)  1lcj: SH2 (SRC HOMOLOGY-2) DOMAIN OF HUMAN P56-LCK TYROSINE KINASE COMPLEXED WITH THE 11 RESIDUE PHOSPHOTYROSYL PEPTIDE EPQPYEEIPIYL  1lck: SH3-SH2 DOMAIN FRAGMENT OF HUMAN P56-LCK TYROSINE KINASE COMPLEXED WITH THE 10 RESIDUE SYNTHETIC PHOSPHOTYROSYL PEPTIDE TEGQPYQPQPA  1lkk: HUMAN P56-LCK TYROSINE KINASE SH2 DOMAIN IN COMPLEX WITH THE PHOSPHOTYROSYL PEPTIDE AC-PTYR-GLU-GLU-ILE (PYEEI PEPTIDE)  1lkl: HUMAN P56-LCK TYROSINE KINASE SH2 DOMAIN IN COMPLEX WITH THE PHOSPHOTYROSYL PEPTIDE AC-PTYR-GLU-GLU-GLY (PYEEG PEPTIDE)  1q68: Solution structure of T-cell surface glycoprotein CD4 and Proto-oncogene tyrosine-protein kinase LCK fragments  1q69: Solution structure of T-cell surface glycoprotein CD8 alpha chain and Proto-oncogene tyrosine-protein kinase LCK fragments  1qpc: STRUCTURAL ANALYSIS OF THE LYMPHOCYTE-SPECIFIC KINASE LCK IN COMPLEX WITH NON-SELECTIVE AND SRC FAMILY SELECTIVE KINASE INHIBITORS  1qpd: STRUCTURAL ANALYSIS OF THE LYMPHOCYTE-SPECIFIC KINASE LCK IN COMPLEX WITH NON-SELECTIVE AND SRC FAMILY SELECTIVE KINASE INHIBITORS  1qpe: STRUCTURAL ANALYSIS OF THE LYMPHOCYTE-SPECIFIC KINASE LCK IN COMPLEX WITH NON-SELECTIVE AND SRC FAMILY SELECTIVE KINASE INHIBITORS  1qpj: CRYSTAL STRUCTURE OF THE LYMPHOCYTE-SPECIFIC KINASE LCK IN COMPLEX WITH STAUROSPORINE.  1x27: Crystal Structure of Lck SH2-SH3 with SH2 binding site of p130Cas  2iim: SH3 Domain of Human Lck  2of2: crystal structure of furanopyrimidine 8 bound to lck  2of4: crystal structure of furanopyrimidine 1 bound to lck  2ofu: x-ray crystal structure of 2-aminopyrimidine carbamate 43 bound to Lck  2ofv: crystal structure of aminoquinazoline 1 bound to Lck  2og8: crystal structure of aminoquinazoline 36 bound to Lck  3lck: THE KINASE DOMAIN OF HUMAN LYMPHOCYTE KINASE (LCK), ACTIVATED FORM (AUTO-PHOSPHORYLATED ON TYR394)