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Protein

Proto-oncogene tyrosine-protein kinase LCK

Gene

Lck

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein 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)DescriptionActionsGraphical viewLength
Binding sitei273ATPPROSITE-ProRule annotation1
Active sitei364Proton acceptorPROSITE-ProRule annotation1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi251 – 259ATPPROSITE-ProRule annotation9

GO - Molecular functioni

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Kinase, Transferase, Tyrosine-protein kinase

Keywords - Ligandi

ATP-binding, Nucleotide-binding

Enzyme and pathway databases

BRENDAi2.7.10.2. 3474.
ReactomeiR-MMU-114604. GPVI-mediated activation cascade.
R-MMU-1257604. PIP3 activates AKT signaling.
R-MMU-1433557. Signaling by SCF-KIT.
R-MMU-1433559. Regulation of KIT signaling.
R-MMU-202424. Downstream TCR signaling.
R-MMU-202427. Phosphorylation of CD3 and TCR zeta chains.
R-MMU-202430. Translocation of ZAP-70 to Immunological synapse.
R-MMU-202433. Generation of second messenger molecules.
R-MMU-2424491. DAP12 signaling.
R-MMU-389356. CD28 co-stimulation.
R-MMU-389357. CD28 dependent PI3K/Akt signaling.
R-MMU-389359. CD28 dependent Vav1 pathway.
R-MMU-389513. CTLA4 inhibitory signaling.
R-MMU-389948. PD-1 signaling.
R-MMU-451927. Interleukin-2 signaling.
R-MMU-6811558. PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling.

Names & Taxonomyi

Protein namesi
Recommended name:
Proto-oncogene tyrosine-protein kinase LCK (EC:2.7.10.2)
Alternative name(s):
Leukocyte C-terminal Src kinase
Short name:
LSK
Lymphocyte cell-specific protein-tyrosine kinase
p56-LCK
Gene namesi
Name:Lck
Synonyms:Lsk-t
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 4

Organism-specific databases

MGIiMGI:96756. Lck.

Subcellular locationi

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Cytoplasm, Membrane

Pathology & Biotechi

Disruption phenotypei

Mice show a dramatic reduction in the level of peripheral T-cells, with 5-10% of wild-type levels. T-cells also exhibit a 10-fold decrease in proliferative response.1 Publication

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi2G → A: Abolishes myristoylation and palmitoylation. 1 Publication1
Mutagenesisi3 – 5CVC → SVK: Complete loss of interaction with CD4 or CD8. 1 Publication3
Mutagenesisi3C → S: Abolishes plasma membrane association; when associated with S-41. Reduced palmitoylation level. 2 Publications1
Mutagenesisi5C → K: Reduced palmitoylation level. 2 Publications1
Mutagenesisi5C → S: Abolishes plasma membrane association; when associated with S-21. 2 Publications1
Mutagenesisi20C → S: Complete loss of interaction with CD4 or CD8. 1 Publication1
Mutagenesisi23C → S: Complete loss of interaction with CD4 or CD8. 1 Publication1
Mutagenesisi269K → N: Reduced activity. 1
Mutagenesisi270V → L: Reduced activity. 1
Mutagenesisi271A → S: Reduced activity. 1
Mutagenesisi272V → A: Reduced activity. 1
Mutagenesisi273K → R: Loss of activity. 1 Publication1
Mutagenesisi274S → N: Reduced activity. 1
Mutagenesisi275L → M: Reduced activity. 1
Mutagenesisi276K → V: Reduced activity. 1
Mutagenesisi505Y → F: Causes thymic tumors. 2 Publications1

Keywords - Diseasei

Proto-oncogene

Chemistry databases

ChEMBLiCHEMBL2480.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Initiator methionineiRemovedCurated
ChainiPRO_00000881252 – 509Proto-oncogene tyrosine-protein kinase LCKAdd BLAST508

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Lipidationi2N-myristoyl glycine1 Publication1
Lipidationi3S-palmitoyl cysteine2 Publications1
Lipidationi5S-palmitoyl cysteine2 Publications1
Modified residuei102PhosphoserineBy similarity1
Modified residuei159PhosphothreonineBy similarity1
Modified residuei162PhosphoserineBy similarity1
Modified residuei192PhosphotyrosineCombined sources1
Modified residuei194PhosphoserineBy similarity1
Modified residuei394Phosphotyrosine; by autocatalysis1 Publication1
Modified residuei505Phosphotyrosine; by CSKBy similarity1

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.2 Publications
Palmitoylation regulates subcellular location.By similarity

Keywords - PTMi

Lipoprotein, Myristate, Palmitate, Phosphoprotein

Proteomic databases

EPDiP06240.
MaxQBiP06240.
PaxDbiP06240.
PRIDEiP06240.

PTM databases

iPTMnetiP06240.
PhosphoSitePlusiP06240.
SwissPalmiP06240.

Expressioni

Tissue specificityi

Present at a low level in most T-cells, and at an elevated level in LSTRA and Thy19 (T-cell lymphoma) cells.

Developmental stagei

Levels remain relatively constant throughout T-cell ontogeny.

Gene expression databases

BgeeiENSMUSG00000000409.
CleanExiMM_LCK.
ExpressionAtlasiP06240. baseline and differential.
GenevisibleiP06240. MM.

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 phosphorylation in the presence of functional ZAP70. Interacts with CEACAM1 (via cytoplasmic domain); mediates CEACAM1 phosphorylation resulting in PTPN6 recruitment that dephosphorylates TCR stimulation-induced CD247 and ZAP70 (By similarity).By similarity

Binary interactionsi

WithEntry#Exp.IntActNotes
O929722EBI-1401,EBI-710506From a different organism.
P279583EBI-1401,EBI-706378From a different organism.
Cd4P063323EBI-1401,EBI-1404
Cd8aP017312EBI-1401,EBI-1433
KHDRBS1Q076662EBI-1401,EBI-1364From a different organism.
PTPRCP085752EBI-1401,EBI-1341From a different organism.
PtprcP068003EBI-1401,EBI-1672
Sh2d2aQ9QXK93EBI-1401,EBI-1644

GO - Molecular functioni

Protein-protein interaction databases

BioGridi201120. 28 interactors.
IntActiP06240. 33 interactors.
MINTiMINT-85459.
STRINGi10090.ENSMUSP00000125777.

Chemistry databases

BindingDBiP06240.

Structurei

3D structure databases

ProteinModelPortaliP06240.
SMRiP06240.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini61 – 121SH3PROSITE-ProRule annotationAdd BLAST61
Domaini127 – 224SH2PROSITE-ProRule annotationAdd BLAST98
Domaini245 – 498Protein kinasePROSITE-ProRule annotationAdd BLAST254

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni2 – 72Interactions with CD4 and CD8Add BLAST71
Regioni154 – 242Interaction with PTPRHBy similarityAdd BLAST89

Domaini

The SH2 domain mediates interaction with SQSTM1. Interaction is regulated by Ser-59 phosphorylation (By similarity).By similarity

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

SH2 domain, SH3 domain

Phylogenomic databases

eggNOGiKOG0197. Eukaryota.
COG0515. LUCA.
GeneTreeiENSGT00760000118938.
HOGENOMiHOG000233858.
HOVERGENiHBG008761.
InParanoidiP06240.
KOiK05856.
PhylomeDBiP06240.
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.

P06240-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MGCVCSSNPE DDWMENIDVC ENCHYPIVPL DSKISLPIRN 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
QNLERGYRMV RPDNCPEELY HLMMLCWKER PEDRPTFDYL RSVLDDFFTA

TEGQYQPQP
Length:509
Mass (Da):57,943
Last modified:January 23, 2007 - v4
Checksum:i3513102F49A7FD0B
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
M12056 mRNA. Translation: AAB59674.1.
X03533 mRNA. Translation: CAA27234.1.
X03533 mRNA. Translation: CAA27235.1. Sequence problems.
X03533 mRNA. Translation: CAA27236.1. Sequence problems.
AK088001 mRNA. Translation: BAC40086.1.
BC011474 mRNA. Translation: AAH11474.1.
M21511 Genomic DNA. Translation: AAA39422.1. Sequence problems.
M18098 Genomic DNA. Translation: AAA39421.1.
CCDSiCCDS18697.1.
PIRiI48845.
RefSeqiNP_001155905.1. NM_001162433.1.
NP_034823.1. NM_010693.3.
XP_006502881.1. XM_006502818.3.
UniGeneiMm.293753.

Genome annotation databases

EnsembliENSMUST00000067240; ENSMUSP00000066209; ENSMUSG00000000409.
ENSMUST00000102596; ENSMUSP00000099656; ENSMUSG00000000409.
GeneIDi16818.
KEGGimmu:16818.
UCSCiuc008uxi.2. mouse.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
M12056 mRNA. Translation: AAB59674.1.
X03533 mRNA. Translation: CAA27234.1.
X03533 mRNA. Translation: CAA27235.1. Sequence problems.
X03533 mRNA. Translation: CAA27236.1. Sequence problems.
AK088001 mRNA. Translation: BAC40086.1.
BC011474 mRNA. Translation: AAH11474.1.
M21511 Genomic DNA. Translation: AAA39422.1. Sequence problems.
M18098 Genomic DNA. Translation: AAA39421.1.
CCDSiCCDS18697.1.
PIRiI48845.
RefSeqiNP_001155905.1. NM_001162433.1.
NP_034823.1. NM_010693.3.
XP_006502881.1. XM_006502818.3.
UniGeneiMm.293753.

3D structure databases

ProteinModelPortaliP06240.
SMRiP06240.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi201120. 28 interactors.
IntActiP06240. 33 interactors.
MINTiMINT-85459.
STRINGi10090.ENSMUSP00000125777.

Chemistry databases

BindingDBiP06240.
ChEMBLiCHEMBL2480.

PTM databases

iPTMnetiP06240.
PhosphoSitePlusiP06240.
SwissPalmiP06240.

Proteomic databases

EPDiP06240.
MaxQBiP06240.
PaxDbiP06240.
PRIDEiP06240.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000067240; ENSMUSP00000066209; ENSMUSG00000000409.
ENSMUST00000102596; ENSMUSP00000099656; ENSMUSG00000000409.
GeneIDi16818.
KEGGimmu:16818.
UCSCiuc008uxi.2. mouse.

Organism-specific databases

CTDi3932.
MGIiMGI:96756. Lck.

Phylogenomic databases

eggNOGiKOG0197. Eukaryota.
COG0515. LUCA.
GeneTreeiENSGT00760000118938.
HOGENOMiHOG000233858.
HOVERGENiHBG008761.
InParanoidiP06240.
KOiK05856.
PhylomeDBiP06240.
TreeFamiTF351634.

Enzyme and pathway databases

BRENDAi2.7.10.2. 3474.
ReactomeiR-MMU-114604. GPVI-mediated activation cascade.
R-MMU-1257604. PIP3 activates AKT signaling.
R-MMU-1433557. Signaling by SCF-KIT.
R-MMU-1433559. Regulation of KIT signaling.
R-MMU-202424. Downstream TCR signaling.
R-MMU-202427. Phosphorylation of CD3 and TCR zeta chains.
R-MMU-202430. Translocation of ZAP-70 to Immunological synapse.
R-MMU-202433. Generation of second messenger molecules.
R-MMU-2424491. DAP12 signaling.
R-MMU-389356. CD28 co-stimulation.
R-MMU-389357. CD28 dependent PI3K/Akt signaling.
R-MMU-389359. CD28 dependent Vav1 pathway.
R-MMU-389513. CTLA4 inhibitory signaling.
R-MMU-389948. PD-1 signaling.
R-MMU-451927. Interleukin-2 signaling.
R-MMU-6811558. PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling.

Miscellaneous databases

PROiP06240.
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000000409.
CleanExiMM_LCK.
ExpressionAtlasiP06240. baseline and differential.
GenevisibleiP06240. MM.

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...

Entry informationi

Entry nameiLCK_MOUSE
AccessioniPrimary (citable) accession number: P06240
Secondary accession number(s): Q61794
, Q61795, Q62320, Q91X65
Entry historyi
Integrated into UniProtKB/Swiss-Prot: January 1, 1988
Last sequence update: January 23, 2007
Last modified: November 2, 2016
This is version 195 of the entry and version 4 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. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  3. SIMILARITY comments
    Index of protein domains and families

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 one 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.