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Protein

Proto-oncogene tyrosine-protein kinase LCK

Gene

Lck

Organism
Rattus norvegicus (Rat)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at transcript leveli

Functioni

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). Interacts with UNC119; this interaction plays a crucial role in activation of LCK (By similarity).By similarity

Catalytic activityi

ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.PROSITE-ProRule annotation

Enzyme regulationi

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).By similarity

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Binding sitei273 – 2731ATPPROSITE-ProRule annotation
Active sitei364 – 3641Proton acceptorPROSITE-ProRule annotation

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Nucleotide bindingi251 – 2599ATPPROSITE-ProRule annotation

GO - Molecular functioni

  • antigen binding Source: RGD
  • ATP binding Source: UniProtKB-KW
  • non-membrane spanning protein tyrosine kinase activity Source: GO_Central
  • protein complex binding Source: RGD
  • protein tyrosine kinase activity Source: RGD
  • receptor binding Source: GO_Central

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Kinase, Transferase, Tyrosine-protein kinase

Keywords - Ligandi

ATP-binding, Nucleotide-binding

Enzyme and pathway databases

ReactomeiREACT_274291. Generation of second messenger molecules.
REACT_276807. CD28 dependent PI3K/Akt signaling.
REACT_281751. Translocation of ZAP-70 to Immunological synapse.
REACT_289444. CD28 co-stimulation.
REACT_297589. GPVI-mediated activation cascade.
REACT_299102. PIP3 activates AKT signaling.
REACT_305922. CTLA4 inhibitory signaling.
REACT_313573. Regulation of KIT signaling.
REACT_315814. Interleukin-2 signaling.
REACT_316519. CD28 dependent Vav1 pathway.
REACT_316530. Phosphorylation of CD3 and TCR zeta chains.
REACT_332169. DAP12 signaling.
REACT_335137. Signaling by SCF-KIT.
REACT_342970. Downstream TCR signaling.
REACT_352796. PD-1 signaling.

Names & Taxonomyi

Protein namesi
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 namesi
Name:Lck
OrganismiRattus norvegicus (Rat)
Taxonomic identifieri10116 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus
ProteomesiUP000002494 Componenti: Chromosome 5

Organism-specific databases

RGDi2994. Lck.

Subcellular locationi

GO - Cellular componenti

  • cell-cell junction Source: Ensembl
  • endocytic vesicle Source: RGD
  • extracellular exosome Source: Ensembl
  • extrinsic component of cytoplasmic side of plasma membrane Source: GO_Central
  • immunological synapse Source: Ensembl
  • membrane raft Source: RGD
  • plasma membrane Source: RGD
Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Cytoplasm, Membrane

Pathology & Biotechi

Involvement in diseasei

Proviral insertion upstream of the Lck gene causes overexpression, leading to the development of thymic lymphoma.

Keywords - Diseasei

Proto-oncogene

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Initiator methioninei1 – 11RemovedBy similarity
Chaini2 – 509508Proto-oncogene tyrosine-protein kinase LCKPRO_0000088126Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Lipidationi2 – 21N-myristoyl glycineBy similarity
Lipidationi3 – 31S-palmitoyl cysteineBy similarity
Lipidationi5 – 51S-palmitoyl cysteineBy similarity
Modified residuei6 – 61PhosphoserineBy similarity
Modified residuei35 – 351PhosphothreonineBy similarity
Modified residuei102 – 1021PhosphoserineBy similarity
Modified residuei159 – 1591PhosphothreonineBy similarity
Modified residuei162 – 1621PhosphoserineBy similarity
Modified residuei192 – 1921PhosphotyrosineBy similarity
Modified residuei194 – 1941PhosphoserineBy similarity
Modified residuei263 – 2631PhosphotyrosineBy similarity
Modified residuei304 – 3041PhosphotyrosineBy similarity
Modified residuei313 – 3131PhosphotyrosineBy similarity
Modified residuei394 – 3941Phosphotyrosine; by autocatalysisBy similarity
Modified residuei457 – 4571PhosphotyrosineBy similarity
Modified residuei470 – 4701PhosphotyrosineBy similarity
Modified residuei486 – 4861PhosphothreonineBy similarity
Modified residuei499 – 4991PhosphothreonineBy similarity
Modified residuei505 – 5051Phosphotyrosine; by CSKBy similarity

Post-translational modificationi

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. Dephosphorylation at Tyr-394 by PTPN2 negatively regulates T-cells differentiation (By similarity).By similarity
Myristoylation is required prior to palmitoylation.By similarity
Palmitoylation regulates subcellular location.By similarity

Keywords - PTMi

Lipoprotein, Myristate, Palmitate, Phosphoprotein

Proteomic databases

PaxDbiQ01621.

PTM databases

PhosphoSiteiQ01621.

Expressioni

Gene expression databases

ExpressionAtlasiQ01621. baseline.
GenevestigatoriQ01621.

Interactioni

Subunit structurei

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 presence of a functional ZAP70 (By similarity).By similarity

Protein-protein interaction databases

STRINGi10116.ENSRNOP00000012936.

Structurei

3D structure databases

ProteinModelPortaliQ01621.
SMRiQ01621. Positions 7-35, 64-509.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini61 – 12161SH3PROSITE-ProRule annotationAdd
BLAST
Domaini127 – 22498SH2PROSITE-ProRule annotationAdd
BLAST
Domaini245 – 498254Protein kinasePROSITE-ProRule annotationAdd
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni2 – 7271Interactions with CD4 and CD8By similarityAdd
BLAST
Regioni154 – 24289Interaction with PTPRHBy similarityAdd
BLAST

Sequence similaritiesi

Belongs to the protein kinase superfamily. Tyr protein kinase family. SRC subfamily.PROSITE-ProRule annotation
Contains 1 protein kinase domain.PROSITE-ProRule annotation
Contains 1 SH2 domain.PROSITE-ProRule annotation
Contains 1 SH3 domain.PROSITE-ProRule annotation

Keywords - Domaini

SH3 domain

Phylogenomic databases

eggNOGiCOG0515.
GeneTreeiENSGT00760000118938.
HOGENOMiHOG000233858.
HOVERGENiHBG008761.
InParanoidiQ01621.
KOiK05856.
OMAiDIHESCS.
OrthoDBiEOG7GTT2V.
PhylomeDBiQ01621.
TreeFamiTF351634.

Family and domain databases

Gene3Di3.30.505.10. 1 hit.
InterProiIPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_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]
PfamiPF07714. Pkinase_Tyr. 1 hit.
PF00017. SH2. 1 hit.
PF00018. SH3_1. 1 hit.
[Graphical view]
PRINTSiPR00401. SH2DOMAIN.
PR00452. SH3DOMAIN.
PR00109. TYRKINASE.
SMARTiSM00252. SH2. 1 hit.
SM00326. SH3. 1 hit.
SM00219. TyrKc. 1 hit.
[Graphical view]
SUPFAMiSSF50044. SSF50044. 1 hit.
SSF55550. SSF55550. 1 hit.
SSF56112. SSF56112. 1 hit.
PROSITEiPS00107. 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]

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

Q01621-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MGCVCSSNPE DDWMENIDVC ENCHYPIVPL DSKSTLPIRT GSEVRDPLVT
60 70 80 90 100
YEGSLPPASP LQDNLVIALH SYEPSHDGDL GFEKGEQLRI LEQSGEWWKA
110 120 130 140 150
QSLTTGQEGF IPFNFVAKAN SLEPEPWFFK NLSRKDAERQ LLAPGNTHGS
160 170 180 190 200
FLIRESESTA GSFSLSVRDF DQNQGEVVKH YKIRNLDNGG FYISPRITFP
210 220 230 240 250
GLHDLVRHYT NASDGLCTKL SRPCQTQKPQ KPWWEDEWEV PRETLKLVER
260 270 280 290 300
LGAGQFGEVW MGYYNGHTKV AVKSLKQGSM SPDAFLAEAN LMKQLQHPRL
310 320 330 340 350
VRLYAVVTQE PIYIITEYME NGSLVDFLKT PSGIKLNVNK LLDMAAQIAE
360 370 380 390 400
GMAFIEEQNY IHRDLRAANI LVSDTLSCKI ADFGLARLIE DNEYTAREGA
410 420 430 440 450
KFPIKWTAPE AINYGTFTIK SDVWSFGILL TEIVTHGRIP YPGMTNPEVI
460 470 480 490 500
QNLEKGYRMV RPDNCPEELY HLMMLCWKER PEDRPTFDYL RSVLDDFFTA

TEGQYQPQP
Length:509
Mass (Da):57,890
Last modified:March 24, 2009 - v3
Checksum:iB23F3F4BEF3D6654
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
CH473968 Genomic DNA. Translation: EDL80546.1.
BC160881 mRNA. Translation: AAI60881.1.
Z15029 Genomic DNA. Translation: CAA78748.1.
PIRiI58370. S24780.
RefSeqiNP_001094179.1. NM_001100709.1.
XP_006238995.1. XM_006238933.2.
XP_008762362.1. XM_008764140.1.
UniGeneiRn.22791.

Genome annotation databases

EnsembliENSRNOT00000012936; ENSRNOP00000012936; ENSRNOG00000009705.
GeneIDi313050.
KEGGirno:313050.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
CH473968 Genomic DNA. Translation: EDL80546.1.
BC160881 mRNA. Translation: AAI60881.1.
Z15029 Genomic DNA. Translation: CAA78748.1.
PIRiI58370. S24780.
RefSeqiNP_001094179.1. NM_001100709.1.
XP_006238995.1. XM_006238933.2.
XP_008762362.1. XM_008764140.1.
UniGeneiRn.22791.

3D structure databases

ProteinModelPortaliQ01621.
SMRiQ01621. Positions 7-35, 64-509.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

STRINGi10116.ENSRNOP00000012936.

PTM databases

PhosphoSiteiQ01621.

Proteomic databases

PaxDbiQ01621.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSRNOT00000012936; ENSRNOP00000012936; ENSRNOG00000009705.
GeneIDi313050.
KEGGirno:313050.

Organism-specific databases

CTDi3932.
RGDi2994. Lck.

Phylogenomic databases

eggNOGiCOG0515.
GeneTreeiENSGT00760000118938.
HOGENOMiHOG000233858.
HOVERGENiHBG008761.
InParanoidiQ01621.
KOiK05856.
OMAiDIHESCS.
OrthoDBiEOG7GTT2V.
PhylomeDBiQ01621.
TreeFamiTF351634.

Enzyme and pathway databases

ReactomeiREACT_274291. Generation of second messenger molecules.
REACT_276807. CD28 dependent PI3K/Akt signaling.
REACT_281751. Translocation of ZAP-70 to Immunological synapse.
REACT_289444. CD28 co-stimulation.
REACT_297589. GPVI-mediated activation cascade.
REACT_299102. PIP3 activates AKT signaling.
REACT_305922. CTLA4 inhibitory signaling.
REACT_313573. Regulation of KIT signaling.
REACT_315814. Interleukin-2 signaling.
REACT_316519. CD28 dependent Vav1 pathway.
REACT_316530. Phosphorylation of CD3 and TCR zeta chains.
REACT_332169. DAP12 signaling.
REACT_335137. Signaling by SCF-KIT.
REACT_342970. Downstream TCR signaling.
REACT_352796. PD-1 signaling.

Miscellaneous databases

NextBioi665540.
PROiQ01621.

Gene expression databases

ExpressionAtlasiQ01621. baseline.
GenevestigatoriQ01621.

Family and domain databases

Gene3Di3.30.505.10. 1 hit.
InterProiIPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_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]
PfamiPF07714. Pkinase_Tyr. 1 hit.
PF00017. SH2. 1 hit.
PF00018. SH3_1. 1 hit.
[Graphical view]
PRINTSiPR00401. SH2DOMAIN.
PR00452. SH3DOMAIN.
PR00109. TYRKINASE.
SMARTiSM00252. SH2. 1 hit.
SM00326. SH3. 1 hit.
SM00219. TyrKc. 1 hit.
[Graphical view]
SUPFAMiSSF50044. SSF50044. 1 hit.
SSF55550. SSF55550. 1 hit.
SSF56112. SSF56112. 1 hit.
PROSITEiPS00107. 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]
ProtoNetiSearch...

Publicationsi

« Hide 'large scale' publications
  1. Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C.
    Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
  2. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
    The MGC Project Team
    Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
    Tissue: Thymus.
  3. "Frequent activation of the lck gene by promoter insertion and aberrant splicing in murine leukemia virus-induced rat lymphomas."
    Shin S., Steffen D.L.
    Oncogene 8:141-149(1993) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-18.
    Strain: Fischer.

Entry informationi

Entry nameiLCK_RAT
AccessioniPrimary (citable) accession number: Q01621
Secondary accession number(s): B1H265
Entry historyi
Integrated into UniProtKB/Swiss-Prot: June 1, 1994
Last sequence update: March 24, 2009
Last modified: May 27, 2015
This is version 131 of the entry and version 3 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into Uniref entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.