LCK_SAISC
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 03-AUG-2022, entry version 121.
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: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 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
