LCK_RAT
ID LCK_RAT Reviewed; 509 AA.
AC Q01621; B1H265;
DT 01-JUN-1994, integrated into UniProtKB/Swiss-Prot.
DT 24-MAR-2009, sequence version 3.
DT 03-AUG-2022, entry version 174.
DE RecName: Full=Proto-oncogene tyrosine-protein kinase LCK;
DE EC=2.7.10.2;
DE AltName: Full=Lymphocyte cell-specific protein-tyrosine kinase;
DE AltName: Full=p56-LCK;
GN Name=Lck;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Thymus;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-18.
RC STRAIN=Fischer;
RX PubMed=8423992;
RA Shin S., Steffen D.L.;
RT "Frequent activation of the lck gene by promoter insertion and aberrant
RT splicing in murine leukemia virus-induced rat lymphomas.";
RL Oncogene 8:141-149(1993).
RN [4]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-192 AND TYR-505, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22673903; DOI=10.1038/ncomms1871;
RA Lundby A., Secher A., Lage K., Nordsborg N.B., Dmytriyev A., Lundby C.,
RA Olsen J.V.;
RT "Quantitative maps of protein phosphorylation sites across 14 different rat
RT organs and tissues.";
RL Nat. Commun. 3:876-876(2012).
CC -!- FUNCTION: Non-receptor tyrosine-protein kinase that plays an essential
CC role in the selection and maturation of developing T-cells in the
CC thymus and in the function of mature T-cells. Plays a key role in T-
CC cell antigen receptor (TCR)-linked signal transduction pathways.
CC Constitutively associated with the cytoplasmic portions of the CD4 and
CC CD8 surface receptors. Association of the TCR with a peptide antigen-
CC bound MHC complex facilitates the interaction of CD4 and CD8 with MHC
CC class II and class I molecules, respectively, thereby recruiting the
CC associated LCK protein to the vicinity of the TCR/CD3 complex. LCK then
CC phosphorylates tyrosine residues within the immunoreceptor tyrosine-
CC based activation motifs (ITAM) of the cytoplasmic tails of the TCR-
CC gamma chains and CD3 subunits, initiating the TCR/CD3 signaling
CC pathway. Once stimulated, the TCR recruits the tyrosine kinase ZAP70,
CC that becomes phosphorylated and activated by LCK. Following this, a
CC large number of signaling molecules are recruited, ultimately leading
CC to lymphokine production. LCK also contributes to signaling by other
CC receptor molecules. Associates directly with the cytoplasmic tail of
CC CD2, which leads to hyperphosphorylation and activation of LCK. Also
CC plays a role in the IL2 receptor-linked signaling pathway that controls
CC the T-cell proliferative response. Binding of IL2 to its receptor
CC results in increased activity of LCK. Is expressed at all stages of
CC thymocyte development and is required for the regulation of maturation
CC events that are governed by both pre-TCR and mature alpha beta TCR.
CC Phosphorylates other substrates including RUNX3, PTK2B/PYK2, the
CC microtubule-associated protein MAPT, RHOH or TYROBP (By similarity).
CC Interacts with UNC119; this interaction plays a crucial role in
CC activation of LCK (By similarity). {ECO:0000250}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl-
CC [protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA-
CC COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858,
CC ChEBI:CHEBI:82620, ChEBI:CHEBI:456216; EC=2.7.10.2;
CC Evidence={ECO:0000255|PROSITE-ProRule:PRU10028};
CC -!- ACTIVITY REGULATION: The relative activities of the inhibitory
CC tyrosine-protein kinase CSK and the activating tyrosine-protein
CC phosphatase PTPRC/CD45 determine the level of LCK activity. These
CC interactions allow rapid and efficient activation of LCK in response to
CC TCR stimulation (By similarity). {ECO:0000250}.
CC -!- SUBUNIT: Binds to the cytoplasmic domain of cell surface receptors,
CC such as AXL, CD2, CD4, CD5, CD8, CD44, CD45 and CD122. Also binds to
CC effector molecules, such as PI4K, VAV1, RASA1, FYB1 and to other
CC protein kinases including CDK1, RAF1, ZAP70 and SYK. Binds to
CC phosphatidylinositol 3'-kinase (PI3K) from T-lymphocytes through its
CC SH3 domain and to the tyrosine phosphorylated form of KHDRBS1/p70
CC through its SH2 domain. Interacts with SQSTM1. Interacts with
CC phosphorylated LIME1. Interacts with CBLB and PTPRH. Interacts with
CC RUNX3. Forms a signaling complex with EPHA1, PTK2B AND PI3-KINASE; upon
CC activation by EFNA1 which may regulate T-lymphocytes migration.
CC Associates with ZAP70 and RHOH; these interactions allow LCK-mediated
CC RHOH and CD3 subunit phosphorylations in presence of a functional
CC ZAP70. Interacts with CEACAM1 (via cytoplasmic domain); mediates
CC CEACAM1 phosphorylation resulting in PTPN6 recruitment that
CC dephosphorylates TCR stimulation-induced CD247 and ZAP70. Interacts
CC with FYB2. Interacts with CD160. Interacts with CD48.
CC {ECO:0000250|UniProtKB:P06239}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:P06239};
CC Lipid-anchor {ECO:0000250|UniProtKB:P06239}; Cytoplasmic side
CC {ECO:0000250|UniProtKB:P06239}. Cytoplasm, cytosol
CC {ECO:0000250|UniProtKB:P06239}. Note=Present in lipid rafts in an
CC inactive form. {ECO:0000250|UniProtKB:P06239}.
CC -!- PTM: Autophosphorylated on Tyr-394, increasing enzymatic activity, this
CC site is dephosphorylated by PTN22. Phosphorylated on Tyr-505 by CSK,
CC decreasing activity. Dephosphorylated by PTPRC/CD45. Dephosphorylation
CC at Tyr-394 by PTPN2 negatively regulates T-cells differentiation (By
CC similarity). {ECO:0000250}.
CC -!- PTM: Myristoylation is required prior to palmitoylation. {ECO:0000250}.
CC -!- PTM: Palmitoylation regulates association with the plasma membrane and
CC could be mediated by ZDHHC2. {ECO:0000250|UniProtKB:P06239}.
CC -!- DISEASE: Note=Proviral insertion upstream of the Lck gene causes
CC overexpression, leading to the development of thymic lymphoma.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Tyr protein
CC kinase family. SRC subfamily. {ECO:0000255|PROSITE-ProRule:PRU00159}.
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DR EMBL; CH473968; EDL80546.1; -; Genomic_DNA.
DR EMBL; BC160881; AAI60881.1; -; mRNA.
DR EMBL; Z15029; CAA78748.1; -; Genomic_DNA.
DR PIR; I58370; S24780.
DR RefSeq; NP_001094179.1; NM_001100709.1.
DR RefSeq; XP_006238995.1; XM_006238933.3.
DR RefSeq; XP_008762362.1; XM_008764140.2.
DR AlphaFoldDB; Q01621; -.
DR BMRB; Q01621; -.
DR SMR; Q01621; -.
DR IntAct; Q01621; 3.
DR STRING; 10116.ENSRNOP00000012936; -.
DR iPTMnet; Q01621; -.
DR PhosphoSitePlus; Q01621; -.
DR jPOST; Q01621; -.
DR PaxDb; Q01621; -.
DR PRIDE; Q01621; -.
DR GeneID; 313050; -.
DR KEGG; rno:313050; -.
DR CTD; 3932; -.
DR RGD; 2994; Lck.
DR eggNOG; KOG0197; Eukaryota.
DR HOGENOM; CLU_000288_7_2_1; -.
DR InParanoid; Q01621; -.
DR PhylomeDB; Q01621; -.
DR TreeFam; TF351634; -.
DR Reactome; R-RNO-114604; GPVI-mediated activation cascade.
DR Reactome; R-RNO-1257604; PIP3 activates AKT signaling.
DR Reactome; R-RNO-1433557; Signaling by SCF-KIT.
DR Reactome; R-RNO-1433559; Regulation of KIT signaling.
DR Reactome; R-RNO-202424; Downstream TCR signaling.
DR Reactome; R-RNO-202427; Phosphorylation of CD3 and TCR zeta chains.
DR Reactome; R-RNO-202430; Translocation of ZAP-70 to Immunological synapse.
DR Reactome; R-RNO-202433; Generation of second messenger molecules.
DR Reactome; R-RNO-210990; PECAM1 interactions.
DR Reactome; R-RNO-2424491; DAP12 signaling.
DR Reactome; R-RNO-389356; CD28 co-stimulation.
DR Reactome; R-RNO-389357; CD28 dependent PI3K/Akt signaling.
DR Reactome; R-RNO-389359; CD28 dependent Vav1 pathway.
DR Reactome; R-RNO-389513; CTLA4 inhibitory signaling.
DR Reactome; R-RNO-389948; PD-1 signaling.
DR Reactome; R-RNO-6811558; PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling.
DR Reactome; R-RNO-9013407; RHOH GTPase cycle.
DR Reactome; R-RNO-9020558; Interleukin-2 signaling.
DR Reactome; R-RNO-9706374; FLT3 signaling through SRC family kinases.
DR PRO; PR:Q01621; -.
DR Proteomes; UP000002494; Unplaced.
DR Proteomes; UP000234681; Chromosome 5.
DR Genevisible; Q01621; RN.
DR GO; GO:0005911; C:cell-cell junction; ISO:RGD.
DR GO; GO:0005829; C:cytosol; IEA:UniProtKB-SubCell.
DR GO; GO:0030139; C:endocytic vesicle; IDA:RGD.
DR GO; GO:0031234; C:extrinsic component of cytoplasmic side of plasma membrane; IBA:GO_Central.
DR GO; GO:0098978; C:glutamatergic synapse; IDA:SynGO.
DR GO; GO:0001772; C:immunological synapse; ISO:RGD.
DR GO; GO:0045121; C:membrane raft; IDA:RGD.
DR GO; GO:0000242; C:pericentriolar material; ISO:RGD.
DR GO; GO:0005886; C:plasma membrane; IDA:RGD.
DR GO; GO:0099091; C:postsynaptic specialization, intracellular component; IDA:SynGO.
DR GO; GO:0003823; F:antigen binding; IPI:RGD.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0051117; F:ATPase binding; ISO:RGD.
DR GO; GO:0042609; F:CD4 receptor binding; ISO:RGD.
DR GO; GO:0042610; F:CD8 receptor binding; ISO:RGD.
DR GO; GO:0042802; F:identical protein binding; ISO:RGD.
DR GO; GO:0004715; F:non-membrane spanning protein tyrosine kinase activity; ISO:RGD.
DR GO; GO:0043548; F:phosphatidylinositol 3-kinase binding; ISO:RGD.
DR GO; GO:0016004; F:phospholipase activator activity; ISO:RGD.
DR GO; GO:0043274; F:phospholipase binding; ISO:RGD.
DR GO; GO:0001784; F:phosphotyrosine residue binding; ISO:RGD.
DR GO; GO:1990405; F:protein antigen binding; ISO:RGD.
DR GO; GO:0008022; F:protein C-terminus binding; ISO:RGD.
DR GO; GO:0019901; F:protein kinase binding; ISO:RGD.
DR GO; GO:0019903; F:protein phosphatase binding; ISO:RGD.
DR GO; GO:0004722; F:protein serine/threonine phosphatase activity; ISO:RGD.
DR GO; GO:0004713; F:protein tyrosine kinase activity; IDA:RGD.
DR GO; GO:0044877; F:protein-containing complex binding; IDA:RGD.
DR GO; GO:0042169; F:SH2 domain binding; ISO:RGD.
DR GO; GO:0005102; F:signaling receptor binding; IBA:GO_Central.
DR GO; GO:0042608; F:T cell receptor binding; ISO:RGD.
DR GO; GO:0006919; P:activation of cysteine-type endopeptidase activity involved in apoptotic process; ISO:RGD.
DR GO; GO:0007568; P:aging; IEP:RGD.
DR GO; GO:0006915; P:apoptotic process; IEP:RGD.
DR GO; GO:0050853; P:B cell receptor signaling pathway; ISO:RGD.
DR GO; GO:0030154; P:cell differentiation; IBA:GO_Central.
DR GO; GO:0007166; P:cell surface receptor signaling pathway; ISO:RGD.
DR GO; GO:0006882; P:cellular zinc ion homeostasis; ISO:RGD.
DR GO; GO:0038094; P:Fc-gamma receptor signaling pathway; ISO:RGD.
DR GO; GO:0045087; P:innate immune response; IBA:GO_Central.
DR GO; GO:0035556; P:intracellular signal transduction; ISO:RGD.
DR GO; GO:0038083; P:peptidyl-tyrosine autophosphorylation; ISO:RGD.
DR GO; GO:0018108; P:peptidyl-tyrosine phosphorylation; IDA:RGD.
DR GO; GO:0045588; P:positive regulation of gamma-delta T cell differentiation; ISO:RGD.
DR GO; GO:0010628; P:positive regulation of gene expression; ISO:RGD.
DR GO; GO:0034116; P:positive regulation of heterotypic cell-cell adhesion; ISO:RGD.
DR GO; GO:2001244; P:positive regulation of intrinsic apoptotic signaling pathway; ISO:RGD.
DR GO; GO:1903039; P:positive regulation of leukocyte cell-cell adhesion; ISO:RGD.
DR GO; GO:0050870; P:positive regulation of T cell activation; ISO:RGD.
DR GO; GO:0042531; P:positive regulation of tyrosine phosphorylation of STAT protein; ISO:RGD.
DR GO; GO:0070474; P:positive regulation of uterine smooth muscle contraction; IMP:RGD.
DR GO; GO:0046777; P:protein autophosphorylation; IDA:RGD.
DR GO; GO:0006468; P:protein phosphorylation; ISO:RGD.
DR GO; GO:0045589; P:regulation of regulatory T cell differentiation; ISO:RGD.
DR GO; GO:0050856; P:regulation of T cell receptor signaling pathway; ISO:RGD.
DR GO; GO:0051209; P:release of sequestered calcium ion into cytosol; ISO:RGD.
DR GO; GO:0042542; P:response to hydrogen peroxide; IDA:RGD.
DR GO; GO:0009612; P:response to mechanical stimulus; IMP:RGD.
DR GO; GO:0010038; P:response to metal ion; IDA:RGD.
DR GO; GO:0009410; P:response to xenobiotic stimulus; ISO:RGD.
DR GO; GO:0010043; P:response to zinc ion; IEP:RGD.
DR GO; GO:0030217; P:T cell differentiation; ISO:RGD.
DR GO; GO:0007169; P:transmembrane receptor protein tyrosine kinase signaling pathway; IBA:GO_Central.
DR CDD; cd10362; SH2_Src_Lck; 1.
DR CDD; cd12005; SH3_Lck; 1.
DR Gene3D; 3.30.505.10; -; 1.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR035850; Lck_SH2.
DR InterPro; IPR035749; Lck_SH3.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR001245; Ser-Thr/Tyr_kinase_cat_dom.
DR InterPro; IPR000980; SH2.
DR InterPro; IPR036860; SH2_dom_sf.
DR InterPro; IPR036028; SH3-like_dom_sf.
DR InterPro; IPR001452; SH3_domain.
DR InterPro; IPR008266; Tyr_kinase_AS.
DR InterPro; IPR020635; Tyr_kinase_cat_dom.
DR Pfam; PF07714; PK_Tyr_Ser-Thr; 1.
DR Pfam; PF00017; SH2; 1.
DR Pfam; PF00018; SH3_1; 1.
DR PRINTS; PR00401; SH2DOMAIN.
DR PRINTS; PR00452; SH3DOMAIN.
DR PRINTS; PR00109; TYRKINASE.
DR SMART; SM00252; SH2; 1.
DR SMART; SM00326; SH3; 1.
DR SMART; SM00219; TyrKc; 1.
DR SUPFAM; SSF50044; SSF50044; 1.
DR SUPFAM; SSF55550; SSF55550; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00109; PROTEIN_KINASE_TYR; 1.
DR PROSITE; PS50001; SH2; 1.
DR PROSITE; PS50002; SH3; 1.
PE 1: Evidence at protein level;
KW ATP-binding; Cell membrane; Cytoplasm; Kinase; Lipoprotein; Membrane;
KW Myristate; Nucleotide-binding; Palmitate; Phosphoprotein; Proto-oncogene;
KW Reference proteome; SH3 domain; Transferase; Tyrosine-protein kinase.
FT INIT_MET 1
FT /note="Removed"
FT CHAIN 2..509
FT /note="Proto-oncogene tyrosine-protein kinase LCK"
FT /id="PRO_0000088126"
FT DOMAIN 61..121
FT /note="SH3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00192"
FT DOMAIN 127..224
FT /note="SH2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00191"
FT DOMAIN 245..498
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 2..72
FT /note="Interactions with CD4 and CD8"
FT /evidence="ECO:0000250"
FT REGION 154..242
FT /note="Interaction with PTPRH"
FT /evidence="ECO:0000250"
FT ACT_SITE 364
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10028"
FT BINDING 251..259
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 273
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 102
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P06239"
FT MOD_RES 159
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:P06239"
FT MOD_RES 162
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P06239"
FT MOD_RES 192
FT /note="Phosphotyrosine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 194
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P06239"
FT MOD_RES 394
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:P06239"
FT MOD_RES 505
FT /note="Phosphotyrosine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT LIPID 2
FT /note="N-myristoyl glycine"
FT /evidence="ECO:0000250"
FT LIPID 3
FT /note="S-palmitoyl cysteine"
FT /evidence="ECO:0000250"
FT LIPID 5
FT /note="S-palmitoyl cysteine"
FT /evidence="ECO:0000250"
SQ SEQUENCE 509 AA; 57890 MW; B23F3F4BEF3D6654 CRC64;
MGCVCSSNPE DDWMENIDVC ENCHYPIVPL DSKSTLPIRT GSEVRDPLVT YEGSLPPASP
LQDNLVIALH SYEPSHDGDL GFEKGEQLRI LEQSGEWWKA QSLTTGQEGF IPFNFVAKAN
SLEPEPWFFK NLSRKDAERQ LLAPGNTHGS FLIRESESTA GSFSLSVRDF DQNQGEVVKH
YKIRNLDNGG FYISPRITFP GLHDLVRHYT NASDGLCTKL SRPCQTQKPQ KPWWEDEWEV
PRETLKLVER LGAGQFGEVW MGYYNGHTKV AVKSLKQGSM SPDAFLAEAN LMKQLQHPRL
VRLYAVVTQE PIYIITEYME NGSLVDFLKT PSGIKLNVNK LLDMAAQIAE GMAFIEEQNY
IHRDLRAANI LVSDTLSCKI ADFGLARLIE DNEYTAREGA KFPIKWTAPE AINYGTFTIK
SDVWSFGILL TEIVTHGRIP YPGMTNPEVI QNLEKGYRMV RPDNCPEELY HLMMLCWKER
PEDRPTFDYL RSVLDDFFTA TEGQYQPQP
