LCK_AOTNA
ID LCK_AOTNA Reviewed; 509 AA.
AC Q5PXS1;
DT 08-NOV-2005, integrated into UniProtKB/Swiss-Prot.
DT 23-JAN-2007, sequence version 4.
DT 03-AUG-2022, entry version 109.
DE RecName: Full=Tyrosine-protein kinase Lck;
DE EC=2.7.10.2;
DE AltName: Full=Lymphocyte cell-specific protein-tyrosine kinase;
DE AltName: Full=Proto-oncogene Lck;
DE AltName: Full=p56-LCK;
GN Name=LCK;
OS Aotus nancymaae (Ma's night monkey).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Platyrrhini; Aotidae;
OC Aotus.
OX NCBI_TaxID=37293;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Perez-Quintero L.A., Vernot J.P.;
RL Submitted (FEB-2005) to the EMBL/GenBank/DDBJ databases.
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. LIME1. Interacts with CBLB and PTPRH. Interacts
CC with RUNX3. Forms a signaling complex with EPHA1, PTK2B AND PI3-KINASE;
CC upon 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 phosphorylation in the presence of 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 CD160. Interacts with CD48. {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 -!- DOMAIN: The SH2 domain mediates interaction with SQSTM1. Interaction is
CC regulated by Ser-59 phosphorylation (By similarity). {ECO:0000250}.
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 -!- 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; AY821852; AAV70114.2; -; mRNA.
DR RefSeq; XP_012296377.1; XM_012440954.1.
DR RefSeq; XP_012296383.1; XM_012440960.1.
DR AlphaFoldDB; Q5PXS1; -.
DR BMRB; Q5PXS1; -.
DR SMR; Q5PXS1; -.
DR Ensembl; ENSANAT00000052605; ENSANAP00000034541; ENSANAG00000034805.
DR GeneID; 105709116; -.
DR CTD; 3932; -.
DR GeneTree; ENSGT00940000161163; -.
DR OMA; ICEHCNY; -.
DR OrthoDB; 539311at2759; -.
DR Proteomes; UP000233020; Unplaced.
DR GO; GO:0005829; C:cytosol; IEA:UniProtKB-SubCell.
DR GO; GO:0045121; C:membrane raft; ISS:UniProtKB.
DR GO; GO:0000242; C:pericentriolar material; ISS:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0004715; F:non-membrane spanning protein tyrosine kinase activity; IEA:UniProtKB-EC.
DR GO; GO:0004722; F:protein serine/threonine phosphatase activity; ISS:UniProtKB.
DR GO; GO:0004713; F:protein tyrosine kinase activity; ISS:UniProtKB.
DR GO; GO:0042169; F:SH2 domain binding; ISS:UniProtKB.
DR GO; GO:0006919; P:activation of cysteine-type endopeptidase activity involved in apoptotic process; ISS:UniProtKB.
DR GO; GO:0006882; P:cellular zinc ion homeostasis; ISS:UniProtKB.
DR GO; GO:2001244; P:positive regulation of intrinsic apoptotic signaling pathway; ISS:UniProtKB.
DR GO; GO:0050870; P:positive regulation of T cell activation; ISS:UniProtKB.
DR GO; GO:0009410; P:response to xenobiotic stimulus; ISS:UniProtKB.
DR GO; GO:0030217; P:T cell differentiation; ISS:UniProtKB.
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 2: Evidence at transcript level;
KW ATP-binding; Cell membrane; Cytoplasm; Kinase; Lipoprotein; Membrane;
KW Myristate; Nucleotide-binding; Palmitate; Phosphoprotein; Proto-oncogene;
KW Reference proteome; SH2 domain; SH3 domain; Transferase;
KW Tyrosine-protein kinase.
FT INIT_MET 1
FT /note="Removed"
FT CHAIN 2..509
FT /note="Tyrosine-protein kinase Lck"
FT /id="PRO_0000088123"
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:0000250|UniProtKB:P06240"
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; by CSK"
FT /evidence="ECO:0000250|UniProtKB:P06239"
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; 58172 MW; 8B61951BDD070EA4 CRC64;
MGCGCSSHPE DDWMENIDVC ENCHYPIVPL DGKATLLFRN GSEVRDPLVR YEGSNPPASP
LQDNLVIALH SYKPSHDGDL GFEKGEQLRI LEQNGEWWKA QSLTTGQEGF IPFNFVAKAN
SLEPEPWFFK NLSRKDAERQ LLAPGNTHGS FLIRESESTA GSFSLSVRDF DQNQGEVVKH
YKIRNLDNGG FYISPRITFP GLHELVRHYT NASDGLCTRL SRPCQTQKPQ KPWWEDEWEV
PRETLKLVER LGAGQFGEVW MGYYNDHTKV AVKSLKQGSM SPDAFLAEAN LMKQLQHQRL
VRLYAVVTQE PIYIITEYME NGSLVDFLKT PSGIKLTINK LLDMAAQIAE GMAFIEERNY
IHRDLRAANI LVSDTLSCKI ADFGLARLIE DNEYTAREGA KFPIKWTAPE AINYGTFTIK
SDVWSFGILL TEIVTHGRIP YPGMTNPEVI QNLERGYRMV RPDNCPEELY HLMMLCWKER
PEDRPTFDYL RSVLEDFFTA TEGQYQPQP
