ID   LTK_MOUSE               Reviewed;         888 AA.
AC   P08923; A2AQ22;
DT   01-NOV-1988, integrated into UniProtKB/Swiss-Prot.
DT   27-JUL-2011, sequence version 3.
DT   27-MAR-2024, entry version 196.
DE   RecName: Full=Leukocyte tyrosine kinase receptor {ECO:0000303|PubMed:2357970};
DE            EC=2.7.10.1 {ECO:0000250|UniProtKB:P29376, ECO:0000255|PROSITE-ProRule:PRU10028};
DE   Flags: Precursor;
GN   Name=Ltk {ECO:0000303|PubMed:2357970};
OS   Mus musculus (Mouse).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC   Murinae; Mus; Mus.
OX   NCBI_TaxID=10090;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM A), AND TISSUE SPECIFICITY.
RC   STRAIN=BALB/cJ;
RX   PubMed=2357970; DOI=10.1002/j.1460-2075.1990.tb07399.x;
RA   Bernards A., de la Monte S.;
RT   "The ltk receptor tyrosine kinase is expressed in pre-B lymphocytes and
RT   cerebral neurons and uses a non-AUG translational initiator.";
RL   EMBO J. 9:2279-2287(1990).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM A).
RC   STRAIN=BALB/cJ;
RX   PubMed=1662793;
RA   Haase V.H., Snijders A.J., Cooke S.M., Teng M.N., Kaul D., le Beau M.M.,
RA   Bruns G.A., Bernards A.;
RT   "Alternatively spliced ltk mRNA in neurons predicts a receptor with a
RT   larger putative extracellular domain.";
RL   Oncogene 6:2319-2325(1991).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS A; B; C AND D), AND SUBCELLULAR
RP   LOCATION.
RX   PubMed=8380920;
RA   Snijders A.J., Haase V.H., Bernards A.;
RT   "Four tissue-specific mouse ltk mRNAs predict tyrosine kinases that differ
RT   upstream of their transmembrane segment.";
RL   Oncogene 8:27-35(1993).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC   STRAIN=C57BL/6J;
RX   PubMed=19468303; DOI=10.1371/journal.pbio.1000112;
RA   Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X.,
RA   Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y.,
RA   Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S.,
RA   Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R.,
RA   Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K.,
RA   Eichler E.E., Ponting C.P.;
RT   "Lineage-specific biology revealed by a finished genome assembly of the
RT   mouse.";
RL   PLoS Biol. 7:E1000112-E1000112(2009).
RN   [5]
RP   NUCLEOTIDE SEQUENCE [MRNA] OF 260-888 (ISOFORM A), AND SUBCELLULAR
RP   LOCATION.
RX   PubMed=2836739; DOI=10.1038/333672a0;
RA   Ben-Neriah Y., Bauskin A.R.;
RT   "Leukocytes express a novel gene encoding a putative transmembrane protein-
RT   kinase devoid of an extracellular domain.";
RL   Nature 333:672-676(1988).
RN   [6]
RP   SUBCELLULAR LOCATION, AND INTERACTION WITH CALNEXIN (ISOFORM A).
RX   PubMed=8995435; DOI=10.1074/jbc.272.2.1297;
RA   Snijders A.J., Ho S.C., Haase V.H., Pillai S., Bernards A.;
RT   "A lymphocyte-specific Ltk tyrosine kinase isoform is retained in the
RT   endoplasmic reticulum in association with calnexin.";
RL   J. Biol. Chem. 272:1297-1301(1997).
RN   [7]
RP   DISRUPTION PHENOTYPE.
RX   PubMed=22079349; DOI=10.1016/j.pbb.2011.10.024;
RA   Weiss J.B., Xue C., Benice T., Xue L., Morris S.W., Raber J.;
RT   "Anaplastic lymphoma kinase and leukocyte tyrosine kinase: functions and
RT   genetic interactions in learning, memory and adult neurogenesis.";
RL   Pharmacol. Biochem. Behav. 100:566-574(2012).
RN   [8]
RP   VARIANT GLU-746.
RC   STRAIN=NZB;
RX   PubMed=14695357; DOI=10.1093/hmg/ddh020;
RA   Li N., Nakamura K., Jiang Y., Tsurui H., Matsuoka S., Abe M., Ohtsuji M.,
RA   Nishimura H., Kato K., Kawai T., Atsumi T., Koike T., Shirai T., Ueno H.,
RA   Hirose S.;
RT   "Gain-of-function polymorphism in mouse and human Ltk: implications for the
RT   pathogenesis of systemic lupus erythematosus.";
RL   Hum. Mol. Genet. 13:171-179(2004).
CC   -!- FUNCTION: Receptor with a tyrosine-protein kinase activity. Following
CC       activation by ALKAL1 or ALKAL2 ligands at the cell surface, transduces
CC       an extracellular signal into an intracellular response. Ligand-binding
CC       to the extracellular domain induces tyrosine kinase activation, leading
CC       to activation of the mitogen-activated protein kinase (MAPK) pathway
CC       (By similarity). Phosphorylates almost exclusively at the first
CC       tyrosine of the Y-x-x-x-Y-Y motif (By similarity). The exact function
CC       of this protein is not known; studies with chimeric proteins
CC       demonstrate its ability to promote growth and specifically neurite
CC       outgrowth, and cell survival. Involved in regulation of the secretory
CC       pathway involving endoplasmic reticulum (ER) export sites (ERESs) and
CC       ER to Golgi transport (By similarity). {ECO:0000250|UniProtKB:P29376,
CC       ECO:0000250|UniProtKB:Q9UM73}.
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=2.7.10.1;
CC         Evidence={ECO:0000250|UniProtKB:P29376, ECO:0000255|PROSITE-
CC         ProRule:PRU10028};
CC   -!- ACTIVITY REGULATION: Activated by ligand-binding, leading to
CC       homodimerization and autophosphorylation.
CC       {ECO:0000250|UniProtKB:Q9UM73}.
CC   -!- SUBUNIT: Homodimer; homodimerizes following ligand-binding. Part of a
CC       complex including LTK, TNK2 and GRB2, in which GRB2 promotes LTK
CC       recruitment by TNK2. {ECO:0000250|UniProtKB:P29376}.
CC   -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:2836739,
CC       ECO:0000269|PubMed:8995435}; Single-pass type I membrane protein
CC       {ECO:0000255}.
CC   -!- SUBCELLULAR LOCATION: [Isoform A]: Endoplasmic reticulum
CC       {ECO:0000305|PubMed:8380920}. Note=Retained in the endoplasmic
CC       reticulum. {ECO:0000305|PubMed:8380920}.
CC   -!- SUBCELLULAR LOCATION: [Isoform B]: Endoplasmic reticulum
CC       {ECO:0000305|PubMed:8380920}. Note=Retained in the endoplasmic
CC       reticulum. {ECO:0000305|PubMed:8380920}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative promoter usage, Alternative splicing; Named isoforms=4;
CC         Comment=Additional isoforms seem to exist.;
CC       Name=D {ECO:0000303|PubMed:8380920};
CC         IsoId=P08923-1; Sequence=Displayed;
CC       Name=A {ECO:0000303|PubMed:8380920};
CC         IsoId=P08923-2; Sequence=VSP_002950, VSP_002951, VSP_002952;
CC       Name=B {ECO:0000303|PubMed:8380920};
CC         IsoId=P08923-3; Sequence=VSP_002950, VSP_002951;
CC       Name=C {ECO:0000303|PubMed:8380920};
CC         IsoId=P08923-4; Sequence=VSP_002952;
CC   -!- TISSUE SPECIFICITY: Subsets of lymphoid and neuronal cells.
CC       {ECO:0000269|PubMed:2357970}.
CC   -!- PTM: Phosphorylated at tyrosine residues by autocatalysis, which
CC       activates kinase activity. {ECO:0000250|UniProtKB:P29376}.
CC   -!- DISRUPTION PHENOTYPE: Mice do not show any decrease in newborn neurons
CC       (PubMed:22079349). Mice lacking both Alk and Ltk show a strong
CC       reduction in newborn neurons (PubMed:22079349).
CC       {ECO:0000269|PubMed:22079349}.
CC   -!- MISCELLANEOUS: [Isoform D]: May be produced by alternative promoter
CC       usage.
CC   -!- MISCELLANEOUS: [Isoform A]: May be produced by alternative promoter
CC       usage. Starts at a CUG codon. {ECO:0000305}.
CC   -!- MISCELLANEOUS: [Isoform B]: May be produced by alternative promoter
CC       usage. Starts at a CUG codon. {ECO:0000305}.
CC   -!- SIMILARITY: Belongs to the protein kinase superfamily. Tyr protein
CC       kinase family. Insulin receptor subfamily. {ECO:0000255|PROSITE-
CC       ProRule:PRU00159}.
CC   -!- SEQUENCE CAUTION:
CC       Sequence=CAA30793.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
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DR   EMBL; X52621; CAA36848.1; -; mRNA.
DR   EMBL; M90470; AAA39451.1; -; mRNA.
DR   EMBL; AL844536; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; X07984; CAA30793.1; ALT_INIT; mRNA.
DR   CCDS; CCDS16608.1; -. [P08923-1]
DR   CCDS; CCDS16609.1; -. [P08923-4]
DR   CCDS; CCDS50674.1; -. [P08923-2]
DR   PIR; I58378; I58378.
DR   PIR; S12792; S12792.
DR   RefSeq; NP_976220.2; NM_203345.2. [P08923-1]
DR   RefSeq; NP_996824.1; NM_206941.1. [P08923-3]
DR   RefSeq; NP_996825.2; NM_206942.2. [P08923-4]
DR   AlphaFoldDB; P08923; -.
DR   SMR; P08923; -.
DR   STRING; 10090.ENSMUSP00000028759; -.
DR   GlyCosmos; P08923; 2 sites, No reported glycans.
DR   GlyGen; P08923; 2 sites.
DR   iPTMnet; P08923; -.
DR   PhosphoSitePlus; P08923; -.
DR   MaxQB; P08923; -.
DR   PaxDb; 10090-ENSMUSP00000028759; -.
DR   Antibodypedia; 23318; 340 antibodies from 32 providers.
DR   DNASU; 17005; -.
DR   Ensembl; ENSMUST00000028759.13; ENSMUSP00000028759.7; ENSMUSG00000027297.16. [P08923-1]
DR   Ensembl; ENSMUST00000082130.13; ENSMUSP00000080774.7; ENSMUSG00000027297.16. [P08923-4]
DR   GeneID; 17005; -.
DR   KEGG; mmu:17005; -.
DR   UCSC; uc008lug.1; mouse. [P08923-3]
DR   UCSC; uc008lui.1; mouse. [P08923-1]
DR   UCSC; uc008luj.1; mouse. [P08923-4]
DR   AGR; MGI:96840; -.
DR   CTD; 4058; -.
DR   MGI; MGI:96840; Ltk.
DR   VEuPathDB; HostDB:ENSMUSG00000027297; -.
DR   eggNOG; KOG1095; Eukaryota.
DR   GeneTree; ENSGT00940000162680; -.
DR   InParanoid; P08923; -.
DR   OMA; WPFGLPE; -.
DR   OrthoDB; 1614410at2759; -.
DR   PhylomeDB; P08923; -.
DR   TreeFam; TF351636; -.
DR   BRENDA; 2.7.10.1; 3474.
DR   BioGRID-ORCS; 17005; 2 hits in 81 CRISPR screens.
DR   PRO; PR:P08923; -.
DR   Proteomes; UP000000589; Chromosome 2.
DR   RNAct; P08923; Protein.
DR   Bgee; ENSMUSG00000027297; Expressed in perirhinal cortex and 88 other cell types or tissues.
DR   ExpressionAtlas; P08923; baseline and differential.
DR   GO; GO:0005783; C:endoplasmic reticulum; IEA:UniProtKB-SubCell.
DR   GO; GO:0016020; C:membrane; IDA:MGI.
DR   GO; GO:0005886; C:plasma membrane; ISO:MGI.
DR   GO; GO:0043235; C:receptor complex; IBA:GO_Central.
DR   GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR   GO; GO:0004672; F:protein kinase activity; ISS:UniProtKB.
DR   GO; GO:0030298; F:receptor signaling protein tyrosine kinase activator activity; ISS:UniProtKB.
DR   GO; GO:0004714; F:transmembrane receptor protein tyrosine kinase activity; ISO:MGI.
DR   GO; GO:0008283; P:cell population proliferation; ISS:UniProtKB.
DR   GO; GO:0071300; P:cellular response to retinoic acid; ISO:MGI.
DR   GO; GO:0043066; P:negative regulation of apoptotic process; ISS:UniProtKB.
DR   GO; GO:0038083; P:peptidyl-tyrosine autophosphorylation; ISS:UniProtKB.
DR   GO; GO:0010666; P:positive regulation of cardiac muscle cell apoptotic process; ISO:MGI.
DR   GO; GO:0010976; P:positive regulation of neuron projection development; ISO:MGI.
DR   GO; GO:0051897; P:positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction; ISS:UniProtKB.
DR   GO; GO:0042127; P:regulation of cell population proliferation; IBA:GO_Central.
DR   GO; GO:0045664; P:regulation of neuron differentiation; IBA:GO_Central.
DR   GO; GO:0007169; P:transmembrane receptor protein tyrosine kinase signaling pathway; ISO:MGI.
DR   CDD; cd05036; PTKc_ALK_LTK; 1.
DR   Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1.
DR   InterPro; IPR011009; Kinase-like_dom_sf.
DR   InterPro; IPR000719; Prot_kinase_dom.
DR   InterPro; IPR017441; Protein_kinase_ATP_BS.
DR   InterPro; IPR001245; Ser-Thr/Tyr_kinase_cat_dom.
DR   InterPro; IPR008266; Tyr_kinase_AS.
DR   InterPro; IPR020635; Tyr_kinase_cat_dom.
DR   InterPro; IPR002011; Tyr_kinase_rcpt_2_CS.
DR   PANTHER; PTHR24416:SF294; LEUKOCYTE TYROSINE KINASE RECEPTOR; 1.
DR   PANTHER; PTHR24416; TYROSINE-PROTEIN KINASE RECEPTOR; 1.
DR   Pfam; PF12810; Gly_rich; 1.
DR   Pfam; PF07714; PK_Tyr_Ser-Thr; 1.
DR   PRINTS; PR00109; TYRKINASE.
DR   SMART; SM00219; TyrKc; 1.
DR   SUPFAM; SSF56112; Protein kinase-like (PK-like); 1.
DR   PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR   PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR   PROSITE; PS00109; PROTEIN_KINASE_TYR; 1.
DR   PROSITE; PS00239; RECEPTOR_TYR_KIN_II; 1.
DR   Genevisible; P08923; MM.
PE   1: Evidence at protein level;
KW   Alternative promoter usage; Alternative splicing; ATP-binding;
KW   Cell membrane; Disulfide bond; Endoplasmic reticulum; Glycoprotein; Kinase;
KW   Membrane; Nucleotide-binding; Phosphoprotein; Receptor; Reference proteome;
KW   Signal; Transferase; Transmembrane; Transmembrane helix;
KW   Tyrosine-protein kinase.
FT   SIGNAL          1..16
FT                   /evidence="ECO:0000255"
FT   CHAIN           17..888
FT                   /note="Leukocyte tyrosine kinase receptor"
FT                   /id="PRO_0000016739"
FT   TOPO_DOM        17..421
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        422..446
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        447..888
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   DOMAIN          506..782
FT                   /note="Protein kinase"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   REGION          226..294
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          857..888
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        235..249
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        873..888
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   ACT_SITE        639
FT                   /note="Proton acceptor"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT                   ECO:0000255|PROSITE-ProRule:PRU10028"
FT   BINDING         512..520
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   BINDING         540
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   MOD_RES         672
FT                   /note="Phosphotyrosine; by autocatalysis"
FT                   /evidence="ECO:0000250"
FT   CARBOHYD        377
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        409
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   DISULFID        73..86
FT                   /evidence="ECO:0000250|UniProtKB:P29376"
FT   DISULFID        168..179
FT                   /evidence="ECO:0000250|UniProtKB:P29376"
FT   DISULFID        297..319
FT                   /evidence="ECO:0000250|UniProtKB:P29376"
FT   VAR_SEQ         1..251
FT                   /note="Missing (in isoform A and isoform B)"
FT                   /evidence="ECO:0000303|PubMed:1662793,
FT                   ECO:0000303|PubMed:2357970, ECO:0000303|PubMed:2836739,
FT                   ECO:0000303|PubMed:8380920"
FT                   /id="VSP_002950"
FT   VAR_SEQ         252
FT                   /note="L -> M (in isoform A and isoform B)"
FT                   /evidence="ECO:0000303|PubMed:1662793,
FT                   ECO:0000303|PubMed:2357970, ECO:0000303|PubMed:2836739,
FT                   ECO:0000303|PubMed:8380920"
FT                   /id="VSP_002951"
FT   VAR_SEQ         271..331
FT                   /note="Missing (in isoform A and isoform C)"
FT                   /evidence="ECO:0000303|PubMed:1662793,
FT                   ECO:0000303|PubMed:2357970, ECO:0000303|PubMed:2836739,
FT                   ECO:0000303|PubMed:8380920"
FT                   /id="VSP_002952"
FT   VARIANT         746
FT                   /note="G -> E"
FT                   /evidence="ECO:0000269|PubMed:14695357"
FT   CONFLICT        26
FT                   /note="T -> A (in Ref. 3; AAA39451)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        113
FT                   /note="V -> A (in Ref. 3; AAA39451)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        789
FT                   /note="V -> M (in Ref. 2; CAA36848 and 3; AAA39451)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        875
FT                   /note="H -> Q (in Ref. 2; CAA36848 and 3; AAA39451)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   888 AA;  94471 MW;  7D204A474DEF0AC6 CRC64;
     MGCSHRLLLW LGAAGTILCS NSEFQTPFLT PSLLPVLVLN SQEQKVTPTP SKLEPASLPN
     PLGTRGPWVF NTCGASGRSG PTQTQCDGAY TGSSVMVTVG AAGPLKGVQL WRVPDTGQYL
     ISAYGAAGGK GAQNHLSRAH GIFLSAVFFL RRGEPVYILV GQQGQDACPG GSPESQLVCL
     GESGEHATTY GTERIPGWRR WAGGGGGGGG ATSIFRLRAG EPEPLLVAAG GGGRSYRRRP
     DRGRTQAVPE RLETRAAAPG SGGRGGAAGG GSGWTSRAHS PQAGRSPREG AEGGEGCAEA
     WAALRWAAAG GFGGGGGACA AGGGGGGYRG GDTSESDLLW ADGEDGTSFV HPSGELYLQP
     LAVTEGHGEV EIRKHPNCSH CPFKDCQWQA ELWTAECTCP EGTELAVDNV TCMDLPTTAS
     PLILMGAVVA ALALSLLMMC AVLILVNQKC QGLWGTRLPG PELELSKLRS SAIRTAPNPY
     YCQVGLSPAQ PWPLPPGLTE VSPANVTLLR ALGHGAFGEV YEGLVTGLPG DSSPLPVAIK
     TLPELCSHQD ELDFLMEALI ISKFSHQNIV RCVGLSFRSA PRLILLELMS GGDMKSFLRH
     SRPHPGQLAP LTMQDLLQLA QDIAQGCHYL EENHFIHRDI AARNCLLSCS GASRVAKIGD
     FGMARDIYQA SYYRKGGRTL LPVKWMPPEA LLEGLFTSKT DSWSFGVLLW EIFSLGYMPY
     PGHTNQEVLD FIATGNRMDP PRNCPGPVYR IMTQCWQHQP ELRPDFGSIL ERIQYCTQDP
     DVLNSPLPVE PGPILEEEEA SRLGNRSLEG LRSPKPLELS SQNLKSWGGG LLGSWLPSGL
     KTLKPRCLQP QNIWNPTYGS WTPRGPQGED TGIEHCNGSS SSSIPGIQ
//