Q95KR7 (LCK_SAISC) Reviewed, UniProtKB/Swiss-Prot
Last modified April 3, 2013. Version 85. History...
Names and origin
|Protein names||Recommended name:|
Proto-oncogene tyrosine-protein kinase LCK
Lymphocyte cell-specific protein-tyrosine kinase
|Organism||Saimiri sciureus (Common squirrel monkey)|
|Taxonomic identifier||9521 [NCBI]|
|Taxonomic lineage||Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Platyrrhini › Cebidae › Saimiriinae › Saimiri|
|Sequence length||509 AA.|
|Protein existence||Evidence at protein level|
General annotation (Comments)
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 tyrosines 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 By similarity.
ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.
The relative activities of the inhibitory tyrosine-protein kinase CSK and the activating tyrosine-protein phosphatase PTPRC/CD45 determine the level of LCK activity. These interactions allow rapid and efficient activation of LCK in response to TCR stimulation By similarity. Ref.1
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, FYB 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. 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-lymphocytes migration. Associates with ZAP70 and RHOH; these interactions allow LCK-mediated RHOH and CD3 subunit phosphorylations in the presence of functional ZAP70 By similarity. Interacts with Saimiriine herpesvirus 2 TIP. Ref.1
Expressed specifically in lymphoid cells.
Levels remain relatively constant throughout T-cell ontogeny.
The SH2 domain mediates interaction with SQSTM1. Interaction is regulated by Ser-59 phosphorylation By similarity.
Autophosphorylated on Tyr-394, increasing enzymatic activity, this site is dephosphorylated by PTN22. Phosphorylated on Tyr-505 by CSK, decreasing activity. Dephosphorylated by PTPRC/CD45 By similarity.
Myristoylation is required prior to palmitoylation By similarity.
Palmitoylation regulates subcellular location By similarity.
Contains 1 protein kinase domain.
Contains 1 SH2 domain.
Contains 1 SH3 domain.
LCK seems to be active in all vertebrates, except in squirrel monkey T-cells, in which it is inactivated. The reason seems to be that squirrel monkeys are the natural host for Saimiriine herpesvirus 2, which is able to efficiently transform T-cells through a mechanism involving viral Tip/ host LCK interaction. Its inactivation may a mechanism that specifically counteracts the transformation effects of viral Tip.
Sequence annotation (Features)
|Feature key||Position(s)||Length||Description||Graphical view||Feature identifier|
|Chain||1 – 509||509||Proto-oncogene tyrosine-protein kinase LCK||PRO_0000088127|
|Domain||61 – 121||61||SH3|
|Domain||127 – 224||98||SH2|
|Domain||245 – 498||254||Protein kinase|
|Nucleotide binding||251 – 259||9||ATP By similarity|
|Region||1 – 72||72||Interactions with CD4 and CD8 By similarity|
|Region||154 – 242||89||Interaction with PTPRH By similarity|
|Active site||364||1||Proton acceptor By similarity|
|Binding site||273||1||ATP By similarity|
Amino acid modifications
|Modified residue||102||1||Phosphoserine By similarity|
|Modified residue||159||1||Phosphothreonine By similarity|
|Modified residue||162||1||Phosphoserine By similarity|
|Modified residue||194||1||Phosphoserine By similarity|
|Modified residue||394||1||Phosphotyrosine; by autocatalysis By similarity|
|Modified residue||505||1||Phosphotyrosine; by CSK By similarity|
|Lipidation||2||1||N-myristoyl glycine By similarity|
|Lipidation||3||1||S-palmitoyl cysteine By similarity|
|Lipidation||5||1||S-palmitoyl cysteine By similarity|
|||"Downregulation of p56Lck tyrosine kinase activity in T cells of squirrel monkeys (Saimiri sciureus) correlates with the non-transforming and apathogenic properties of herpesvirus saimiri in its natural host."|
Greve T., Tamgueney G., Fleischer B., Fickenscher H., Broeker B.M.
J. Virol. 75:9252-9261(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], ENZYME REGULATION, INTERACTION WITH SAIMIRIINE HERPESVIRUS 2 TIP.
|AJ277921 mRNA. Translation: CAC38871.1.|
3D structure databases
|SMR||Q95KR7. Positions 7-35, 65-509. |
Protocols and materials databases
Family and domain databases
|Gene3D||3.30.505.10. 1 hit. |
|InterPro||IPR011009. Kinase-like_dom. |
|Pfam||PF07714. Pkinase_Tyr. 1 hit. |
PF00017. SH2. 1 hit.
PF00018. SH3_1. 1 hit.
|PRINTS||PR00401. SH2DOMAIN. |
|SMART||SM00252. SH2. 1 hit. |
SM00326. SH3. 1 hit.
SM00219. TyrKc. 1 hit.
|SUPFAM||SSF56112. Kinase_like. 1 hit. |
SSF50044. SH3. 1 hit.
|PROSITE||PS00107. PROTEIN_KINASE_ATP. 1 hit. |
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00109. PROTEIN_KINASE_TYR. 1 hit.
PS50001. SH2. 1 hit.
PS50002. SH3. 1 hit.
|Accession||Primary (citable) accession number: Q95KR7|
|Entry status||Reviewed (UniProtKB/Swiss-Prot)|
|Annotation program||Chordata Protein Annotation Program|
Index of protein domains and families