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UniProtKB - P06240 (LCK_MOUSE)

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Protein

Proto-oncogene tyrosine-protein kinase LCK

Gene

Lck

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: -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 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 (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

View the complete GO annotation on QuickGO ...

GO - Biological processi

View the complete GO annotation on QuickGO ...

Keywordsi

Molecular functionKinase, Transferase, Tyrosine-protein kinase
LigandATP-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-6811558 PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling
R-MMU-9020558 Interleukin-2 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 lineageiEukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Myomorpha › Muroidea › Muridae › Murinae › Mus › Mus
Proteomesi
  • UP000000589 Componenti: Chromosome 4

Organism-specific databases

MGIiMGI:96756 Lck

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

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 autocatalysisBy similarity1
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, 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. 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. Interacts with FYB2 (By similarity).By similarity

Binary interactionsi

Show more details

GO - Molecular functioni

View the complete GO annotation on QuickGO ...

Protein-protein interaction databases

BioGridi201120, 28 interactors
CORUMiP06240
ELMiP06240
IntActiP06240, 38 interactors
MINTiP06240
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

Keywords - Domaini

SH2 domain, SH3 domain

Phylogenomic databases

eggNOGiKOG0197 Eukaryota
COG0515 LUCA
GeneTreeiENSGT00760000118938
HOGENOMiHOG000233858
HOVERGENiHBG008761
InParanoidiP06240
KOiK05856
PhylomeDBiP06240
TreeFamiTF351634

Family and domain databases

CDDicd10362 SH2_Src_Lck, 1 hit
cd12005 SH3_Lck, 1 hit
Gene3Di3.30.505.10, 1 hit
InterProiView protein in InterPro
IPR011009 Kinase-like_dom_sf
IPR035850 Lck_SH2
IPR035749 Lck_SH3
IPR000719 Prot_kinase_dom
IPR017441 Protein_kinase_ATP_BS
IPR001245 Ser-Thr/Tyr_kinase_cat_dom
IPR000980 SH2
IPR036860 SH2_dom_sf
IPR036028 SH3-like_dom_sf
IPR001452 SH3_domain
IPR008266 Tyr_kinase_AS
IPR020635 Tyr_kinase_cat_dom
PfamiView protein in Pfam
PF07714 Pkinase_Tyr, 1 hit
PF00017 SH2, 1 hit
PF00018 SH3_1, 1 hit
PRINTSiPR00401 SH2DOMAIN
PR00452 SH3DOMAIN
PR00109 TYRKINASE
SMARTiView protein in SMART
SM00252 SH2, 1 hit
SM00326 SH3, 1 hit
SM00219 TyrKc, 1 hit
SUPFAMiSSF50044 SSF50044, 1 hit
SSF55550 SSF55550, 1 hit
SSF56112 SSF56112, 1 hit
PROSITEiView protein in 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

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

Similar proteinsi

Entry informationi

Entry nameiLCK_MOUSE
AccessioniPrimary (citable) accession number: P06240
Secondary accession number(s): Q61794
, Q61795, Q62320, Q91X65
Entry historyiIntegrated into UniProtKB/Swiss-Prot: January 1, 1988
Last sequence update: January 23, 2007
Last modified: July 18, 2018
This is version 212 of the entry and version 4 of the sequence. See 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

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