Molecular Target Synopsis
Overview
Domains and Structures
Drugs and Clinical Candidates
Druggability
Chemistry
Ligand Efficiency Plot
Pathways
Family Cladogram
Interaction Network
Gene Expression
Gene Copy Number Variation
RNAi
Mutations
Germline Genetics

LCK (P06239) - Overview - Molecular Target Synopsis

Protein


LCK, Tyrosine-protein kinase Lck
Enzyme Classification 2.7.10.2
UniProt P06239

Also Known as LCK_HUMAN, LCK

Non-receptor tyrosine-protein kinase that plays an essential role in the selection and maturation of developing T-cells in the thymus and in the function of mature T-cells. Plays a key role in T-cell antigen receptor (TCR)-linked signal transduction pathways. Constitutively associated with the cytoplasmic portions of the CD4 and CD8 surface receptors. Association of the TCR with a peptide antigen-bound MHC complex facilitates the interaction of CD4 and CD8 with MHC class II and class I molecules, respectively, thereby recruiting the associated LCK protein to the vicinity of the TCR/CD3 complex. LCK then phosphorylates tyrosine residues within the immunoreceptor tyrosine-based activation motifs (ITAM) of the cytoplasmic tails of the TCR-gamma chains and CD3 subunits, initiating the TCR/CD3 signaling pathway. Once stimulated, the TCR recruits the tyrosine kinase ZAP70, that becomes phosphorylated and activated by LCK. Following this, a large number of signaling molecules are recruited, ultimately leading to lymphokine production. LCK also contributes to signaling by other receptor molecules. Associates directly with the cytoplasmic tail of CD2, which leads to hyperphosphorylation and activation of LCK. Also plays a role in the IL2 receptor-linked signaling pathway that controls the T-cell proliferative response. Binding of IL2 to its receptor results in increased activity of LCK. Is expressed at all stages of thymocyte development and is required for the regulation of maturation events that are governed by both pre-TCR and mature alpha beta TCR. Phosphorylates other substrates including RUNX3, PTK2B/PYK2, the microtubule-associated protein MAPT, RHOH or TYROBP. Interacts with FYB2 (PubMed:27335501). Binds to the cytoplasmic domain of cell surface receptors, such as AXL, CD2, CD4, CD5, CD8, CD44, CD45 and CD122. Also binds to effector molecules, such as PI4K, VAV1, RASA1, FYB1 and to other protein kinases including CDK1, RAF1, ZAP70 and SYK. Binds to phosphatidylinositol 3'-kinase (PI3K) from T-lymphocytes through its SH3 domain and to the tyrosine phosphorylated form of KHDRBS1/p70 through its SH2 domain. This interaction inhibits its tyrosine-kinase activity. Interacts with SQSTM1. Interacts with phosphorylated LIME1. Interacts with CBLB and PTPRH. Interacts with RUNX3. Forms a signaling complex with EPHA1, PTK2B AND PI3-KINASE; upon activation by EFNA1 which may regulate T-lymphocyte migration. Associates with ZAP70 and RHOH; these interactions allow LCK-mediated RHOH and CD3 subunit phosphorylation in the presence of functional ZAP70. Interacts with UNC119; this interaction plays a crucial role in activation of LCK. Interacts with CEACAM1 (via cytoplasmic domain); mediates CEACAM1 phosphorylation resulting in PTPN6 recruitment that dephosphorylates TCR stimulation-induced CD247 and ZAP70 (PubMed:18424730). Interacts with CD160.

6H6A
4 RESIDUE FRAGMENT OF
GLY-CYS-GLY-CYS-SER-SER
IN THE STRUCTURE OF
CRYSTAL STRUCTURE OF UNC119 IN COMPLEX WITH LCK PEPTIDE
RCSB/PDB
Inspect Structure
See all 3D Structures for LCK

Isoforms / Transcripts (Protein Coding)


Drugs


LCK is targeted by Approved Drugs Dasatinib, Pazopanib, Vandetanib. (see details)
Dasatinib
Pazopanib
Vandetanib

Sub-cellular localization


UniProt: LCK is active in the following subcellular-locations: cell membrane, cytoplasm.
GO terms: LCK is active in the following subcellular-locations: cytosol, extracellular exosome, extrinsic component of cytoplasmic side of plasma membrane, immunological synapse, membrane raft, pericentriolar material, plasma membrane.



UniProt
GO terms

Gene Copy Number Variation


In COSMIC - Cell Lines Project LCK has gain in 1 cell-lines, loss in 0 cell-lines and no signal in 1004 cell-lines. (see details)

Gene Expression


In NCI60, the highest expressing cell lines are: COLO205, MOLT_4, CCRF_CEM

In Array Express (RNA-seq of 675 commonly used human cancer cell lines), the highest expressing cell lines are: Jurkat, Clone E6-1, COLO 206F, COLO 205

In Array Express (RNA-seq of long poly adenylated RNA and long non poly adenylated RNA from ENCODE cell lines), the highest expressing cell lines are: SK-N-SH, NHLF, HSMM

(see details)

RNA Interference


LCK was reported in the following RNAI studies:

Cell - Large Scale Profiling of Kinase Dependencies in Cancer Cell Lines, the highest RNAi cell lines are: PCI30, H23. (see details)

3D Structures


For LCK there are:
55 structures (69 chains) solved
35 are solved in complex with at least one small molecule ligand
1 are solved with an approved drug

LCK is solved in complex with the approved drug(s):

STI/IMATINIB (2PL0_A).

(see details)
Molecular Target 3D Synopsis

Screening and Chemistry


LCK has been screened with 4437 compounds (7022 bioactivities), 1023 compounds have bioactivities that show binding affinity of <= 500nM (1458 bioactivities). (see details)