Proto-oncogene tyrosine-protein kinase LCK - Saimiri sciureus (Common squirrel monkey)

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Q95KR7 (LCK_SAISC) Reviewed, UniProtKB/Swiss-Prot

Last modified April 3, 2013. Version 85. History...

Clusters with 100%, 90%, 50% identity |

Documents (1) |

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Names·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·Documents Customize order

Names and origin

Protein names

Recommended name:
Proto-oncogene tyrosine-protein kinase LCK
EC=2.7.10.2

Alternative name(s):
Lymphocyte cell-specific protein-tyrosine kinase
p56-LCK

Gene names

Name:

LCK

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

Protein attributes

Sequence length	509 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	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.
Catalytic activity	ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.
Enzyme regulation	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
Subunit structure	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
Subcellular location	Cytoplasm By similarity. Cell membrane; Lipid-anchor; Cytoplasmic side By similarity. Note: Present in lipid rafts in an inactive form By similarity.
Tissue specificity	Expressed specifically in lymphoid cells.
Developmental stage	Levels remain relatively constant throughout T-cell ontogeny.
Domain	The SH2 domain mediates interaction with SQSTM1. Interaction is regulated by Ser-59 phosphorylation By similarity.
Post-translational modification	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.
Sequence similarities	Belongs to the protein kinase superfamily. Tyr protein kinase family. Contains 1 protein kinase domain. Contains 1 SH2 domain. Contains 1 SH3 domain.
Caution	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.

Ontologies

Keywords
Cellular component	Cell membrane Cytoplasm Membrane
Disease	Proto-oncogene
Domain	SH2 domain SH3 domain
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Transferase Tyrosine-protein kinase
PTM	Lipoprotein Myristate Palmitate Phosphoprotein
Gene Ontology (GO)
Biological_process	T cell differentiation Inferred from sequence or structural similarity. Source: UniProtKB activation of cysteine-type endopeptidase activity involved in apoptotic process Inferred from sequence or structural similarity. Source: UniProtKB cellular zinc ion homeostasis Inferred from sequence or structural similarity. Source: UniProtKB induction of apoptosis Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of T cell activation Inferred from sequence or structural similarity. Source: UniProtKB response to drug Inferred from sequence or structural similarity. Source: UniProtKB
Cellular_component	membrane raft Inferred from sequence or structural similarity. Source: UniProtKB pericentriolar material Inferred from sequence or structural similarity. Source: UniProtKB plasma membrane Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW SH2 domain binding Inferred from sequence or structural similarity. Source: UniProtKB non-membrane spanning protein tyrosine kinase activity Inferred from electronic annotation. Source: EC protein serine/threonine phosphatase activity Inferred from sequence or structural similarity. Source: UniProtKB protein tyrosine kinase activity Inferred from sequence or structural similarity. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 509

509

Proto-oncogene tyrosine-protein kinase LCK

PRO_0000088127

Regions

Domain

61 – 121

SH3

Domain

127 – 224

SH2

Domain

245 – 498

254

Protein kinase

Nucleotide binding

251 – 259

ATP By similarity

Region

1 – 72

Interactions with CD4 and CD8 By similarity

Region

154 – 242

Interaction with PTPRH By similarity

Sites

Active site

364

Proton acceptor By similarity

Binding site

273

ATP By similarity

Amino acid modifications

Modified residue

102

Phosphoserine By similarity

Modified residue

159

Phosphothreonine By similarity

Modified residue

162

Phosphoserine By similarity

Modified residue

194

Phosphoserine By similarity

Modified residue

394

Phosphotyrosine; by autocatalysis By similarity

Modified residue

505

Phosphotyrosine; by CSK By similarity

Lipidation

N-myristoyl glycine By similarity

Lipidation

S-palmitoyl cysteine By similarity

Lipidation

S-palmitoyl cysteine By similarity

Sequences

Sequence

Length

Mass (Da)

Tools

Q95KR7 [UniParc].

Last modified January 23, 2007. Version 3.
Checksum: 5088C6407D109519
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FASTA

509

58,253

        10         20         30         40         50         60 
MGCGCSSHLE DDWMENIDVC ENCHYPIVPL DGKATLLFRN GSEVRDPLVR YEGSNPPASP 

        70         80         90        100        110        120 
LQDNLVIALH SYEPSHDGDL GFEKGEHLRI LEQNGEWWKA QSLTTGQEGF VPFNFVAKAN 

       130        140        150        160        170        180 
SLEPEPWFFK NLSRKDAERQ LLAPGNTHGS FLIRESESTA GSFSLSVRDF DQNQGEVVKH 

       190        200        210        220        230        240 
YKIRNLDNGG FYISPRITFS GLHELVRHYT NASDGLCTRL SRPCQTQKPQ KPWWEDEWEV 

       250        260        270        280        290        300 
PRETLKLVER LGAGQFGEVW MGYYNEHTKV AVKSLKQGSM SPDAFLAEAN LMKQLQHKRL 

       310        320        330        340        350        360 
VRLYAVVTEE PIYIITEYME NGSLVDFLKT PSGIKLTINK LLDMAAQIVE GMAFLEERNY 

       370        380        390        400        410        420 
IHRDLRAANI LVSDTLSCKI ADFGLARLIE DNEYTAREGA KFPIKWTAPE AINYGTFTIK 

       430        440        450        460        470        480 
SDVWSFGILM TEIVTHGRIP YPGMTNPEVI QNLERGYRMP RPDNCPEELY KLMMQCWRER 

       490        500 
PDDRPTFDYL RSVLEDFFTA TEGQYQPQP

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References

[1]

"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.
Tissue: T-cell.

Cross-references

Sequence databases
EMBL GenBank DDBJ	AJ277921 mRNA. Translation: CAC38871.1.
3D structure databases
ProteinModelPortal	Q95KR7.
SMR	Q95KR7. Positions 7-35, 65-509.
ModBase	Search...
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Phylogenomic databases
HOVERGEN	HBG008761.
Family and domain databases
Gene3D	3.30.505.10. 1 hit.
InterPro	IPR011009. Kinase-like_dom. IPR000719. Prot_kinase_cat_dom. IPR017441. Protein_kinase_ATP_BS. IPR001245. Ser-Thr/Tyr_kinase_cat_dom. IPR000980. SH2. IPR001452. SH3_domain. IPR008266. Tyr_kinase_AS. IPR020635. Tyr_kinase_cat_dom. [Graphical view]
Pfam	PF07714. Pkinase_Tyr. 1 hit. PF00017. SH2. 1 hit. PF00018. SH3_1. 1 hit. [Graphical view]
PRINTS	PR00401. SH2DOMAIN. PR00452. SH3DOMAIN. PR00109. TYRKINASE.
SMART	SM00252. SH2. 1 hit. SM00326. SH3. 1 hit. SM00219. TyrKc. 1 hit. [Graphical view]
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. [Graphical view]
ProtoNet	Search...

Entry information

Entry name

LCK_SAISC

Accession

Primary (citable) accession number: Q95KR7

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 8, 2005
Last sequence update:	January 23, 2007
Last modified:	April 3, 2013
This is version 85 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

Preferred order of sections

Names and origin

Protein attributes

General annotation (Comments)

Ontologies

Sequence annotation (Features)

Molecule processing

Regions

Sites

Amino acid modifications

Sequences

References

Cross-references

Sequence databases

3D structure databases

Protocols and materials databases

Phylogenomic databases

Family and domain databases

Entry information

Relevant documents