ID   LCK_SAISC               Reviewed;         509 AA.
AC   Q95KR7;
DT   08-NOV-2005, integrated into UniProtKB/Swiss-Prot.
DT   23-JAN-2007, sequence version 3.
DT   08-NOV-2023, entry version 126.
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   Saimiri sciureus (Common squirrel monkey).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Platyrrhini; Cebidae;
OC   Saimiriinae; Saimiri.
OX   NCBI_TaxID=9521;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA], ACTIVITY REGULATION, AND INTERACTION WITH
RP   SAIMIRIINE HERPESVIRUS 2 TIP.
RC   TISSUE=T-cell;
RX   PubMed=11533187; DOI=10.1128/jvi.75.19.9252-9261.2001;
RA   Greve T., Tamgueney G., Fleischer B., Fickenscher H., Broeker B.M.;
RT   "Downregulation of p56Lck tyrosine kinase activity in T cells of squirrel
RT   monkeys (Saimiri sciureus) correlates with the non-transforming and
RT   apathogenic properties of herpesvirus saimiri in its natural host.";
RL   J. Virol. 75:9252-9261(2001).
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       {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 the presence of functional
CC       ZAP70 (By similarity). Interacts with Saimiriine herpesvirus 2 TIP.
CC       Interacts with UNC119; this interaction plays a crucial role in
CC       activation of LCK. Interacts with CEACAM1 (via cytoplasmic domain);
CC       mediates 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   -!- TISSUE SPECIFICITY: Expressed specifically in lymphoid cells.
CC   -!- DEVELOPMENTAL STAGE: Levels remain relatively constant throughout T-
CC       cell ontogeny.
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. {ECO:0000255|PROSITE-ProRule:PRU00159}.
CC   -!- CAUTION: LCK seems to be active in all vertebrates, except in squirrel
CC       monkey T-cells, in which it is inactivated. The reason seems to be that
CC       squirrel monkeys are the natural host for Saimiriine herpesvirus 2,
CC       which is able to efficiently transform T-cells through a mechanism
CC       involving viral Tip/ host LCK interaction. Its inactivation may a
CC       mechanism that specifically counteracts the transformation effects of
CC       viral Tip. {ECO:0000305}.
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DR   EMBL; AJ277921; CAC38871.1; -; mRNA.
DR   AlphaFoldDB; Q95KR7; -.
DR   BMRB; Q95KR7; -.
DR   SMR; Q95KR7; -.
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:intracellular zinc ion homeostasis; ISS:UniProtKB.
DR   GO; GO:0016310; P:phosphorylation; IEA:UniProtKB-KW.
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; cd05067; PTKc_Lck_Blk; 1.
DR   CDD; cd10362; SH2_Src_Lck; 1.
DR   CDD; cd12005; SH3_Lck; 1.
DR   Gene3D; 3.30.505.10; SH2 domain; 1.
DR   Gene3D; 2.30.30.40; SH3 Domains; 1.
DR   Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 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   PANTHER; PTHR24418; TYROSINE-PROTEIN KINASE; 1.
DR   PANTHER; PTHR24418:SF39; TYROSINE-PROTEIN KINASE LCK; 1.
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; SSF56112; Protein kinase-like (PK-like); 1.
DR   SUPFAM; SSF55550; SH2 domain; 1.
DR   SUPFAM; SSF50044; SH3-domain; 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   SH2 domain; 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_0000088127"
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;  58253 MW;  5088C6407D109519 CRC64;
     MGCGCSSHLE DDWMENIDVC ENCHYPIVPL DGKATLLFRN GSEVRDPLVR YEGSNPPASP
     LQDNLVIALH SYEPSHDGDL GFEKGEHLRI LEQNGEWWKA QSLTTGQEGF VPFNFVAKAN
     SLEPEPWFFK NLSRKDAERQ LLAPGNTHGS FLIRESESTA GSFSLSVRDF DQNQGEVVKH
     YKIRNLDNGG FYISPRITFS GLHELVRHYT NASDGLCTRL SRPCQTQKPQ KPWWEDEWEV
     PRETLKLVER LGAGQFGEVW MGYYNEHTKV AVKSLKQGSM SPDAFLAEAN LMKQLQHKRL
     VRLYAVVTEE PIYIITEYME NGSLVDFLKT PSGIKLTINK LLDMAAQIVE GMAFLEERNY
     IHRDLRAANI LVSDTLSCKI ADFGLARLIE DNEYTAREGA KFPIKWTAPE AINYGTFTIK
     SDVWSFGILM TEIVTHGRIP YPGMTNPEVI QNLERGYRMP RPDNCPEELY KLMMQCWRER
     PDDRPTFDYL RSVLEDFFTA TEGQYQPQP
//