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Database: UniProt
Entry: Q60805
LinkDB: Q60805
Original site: Q60805 
ID   MERTK_MOUSE             Reviewed;         994 AA.
AC   Q60805; Q62194;
DT   01-DEC-2000, integrated into UniProtKB/Swiss-Prot.
DT   01-NOV-1996, sequence version 1.
DT   01-OCT-2014, entry version 143.
DE   RecName: Full=Tyrosine-protein kinase Mer;
DE            EC=2.7.10.1;
DE   AltName: Full=Proto-oncogene c-Mer;
DE   AltName: Full=Receptor tyrosine kinase MerTK;
DE   Flags: Precursor;
GN   Name=Mertk; Synonyms=Mer;
OS   Mus musculus (Mouse).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC   Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Sciurognathi;
OC   Muroidea; Muridae; Murinae; Mus; Mus.
OX   NCBI_TaxID=10090;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RC   STRAIN=C57BL/6; TISSUE=Spleen;
RX   PubMed=7784083;
RA   Graham D.K., Bowman G.W., Dawson T.L., Stanford W.L., Earp H.S.,
RA   Snodgrass H.R.;
RT   "Cloning and developmental expression analysis of the murine c-mer
RT   tyrosine kinase.";
RL   Oncogene 10:2349-2359(1995).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA] OF 472-994.
RC   STRAIN=CD-1; TISSUE=Testis;
RA   Dowds C.A., Burks D.J., Saling P.M.;
RT   "A cDNA encoding part of a novel putative receptor tyrosine kinase.";
RL   Submitted (JAN-1996) to the EMBL/GenBank/DDBJ databases.
RN   [3]
RP   DISRUPTION PHENOTYPE.
RX   PubMed=10227296; DOI=10.1038/19554;
RA   Lu Q., Gore M., Zhang Q., Camenisch T., Boast S., Casagranda F.,
RA   Lai C., Skinner M.K., Klein R., Matsushima G.K., Earp H.S., Goff S.P.,
RA   Lemke G.;
RT   "Tyro-3 family receptors are essential regulators of mammalian
RT   spermatogenesis.";
RL   Nature 398:723-728(1999).
RN   [4]
RP   INTERACTION WITH GRB2, AND MUTAGENESIS OF TYR-867.
RX   PubMed=9891051;
RA   Georgescu M.M., Kirsch K.H., Shishido T., Zong C., Hanafusa H.;
RT   "Biological effects of c-Mer receptor tyrosine kinase in hematopoietic
RT   cells depend on the Grb2 binding site in the receptor and activation
RT   of NF-kappaB.";
RL   Mol. Cell. Biol. 19:1171-1181(1999).
RN   [5]
RP   TISSUE SPECIFICITY.
RX   PubMed=12884290; DOI=10.1002/eji.200324076;
RA   Behrens E.M., Gadue P., Gong S.Y., Garrett S., Stein P.L., Cohen P.L.;
RT   "The mer receptor tyrosine kinase: expression and function suggest a
RT   role in innate immunity.";
RL   Eur. J. Immunol. 33:2160-2167(2003).
RN   [6]
RP   INTERACTION WITH PLCG2.
RX   PubMed=14704368; DOI=10.1189/jlb.0903439;
RA   Todt J.C., Hu B., Curtis J.L.;
RT   "The receptor tyrosine kinase MerTK activates phospholipase C gamma2
RT   during recognition of apoptotic thymocytes by murine macrophages.";
RL   J. Leukoc. Biol. 75:705-713(2004).
RN   [7]
RP   INTERACTION WITH FAK/PTK2.
RX   PubMed=15673687; DOI=10.1242/jcs.01632;
RA   Wu Y., Singh S., Georgescu M.M., Birge R.B.;
RT   "A role for Mer tyrosine kinase in alphavbeta5 integrin-mediated
RT   phagocytosis of apoptotic cells.";
RL   J. Cell Sci. 118:539-553(2005).
RN   [8]
RP   PHOSPHORYLATION AT TYR-867.
RX   PubMed=18039660; DOI=10.1074/jbc.M706906200;
RA   Tibrewal N., Wu Y., D'mello V., Akakura R., George T.C., Varnum B.,
RA   Birge R.B.;
RT   "Autophosphorylation docking site Tyr-867 in Mer receptor tyrosine
RT   kinase allows for dissociation of multiple signaling pathways for
RT   phagocytosis of apoptotic cells and down-modulation of
RT   lipopolysaccharide-inducible NF-kappaB transcriptional activation.";
RL   J. Biol. Chem. 283:3618-3627(2008).
RN   [9]
RP   FUNCTION.
RX   PubMed=19117932; DOI=10.1167/iovs.08-3058;
RA   Strick D.J., Feng W., Vollrath D.;
RT   "Mertk drives myosin II redistribution during retinal pigment
RT   epithelial phagocytosis.";
RL   Invest. Ophthalmol. Vis. Sci. 50:2427-2435(2009).
RN   [10]
RP   INTERACTION WITH TUB AND TULP1.
RX   PubMed=20978472; DOI=10.1038/emboj.2010.265;
RA   Caberoy N.B., Zhou Y., Li W.;
RT   "Tubby and tubby-like protein 1 are new MerTK ligands for
RT   phagocytosis.";
RL   EMBO J. 29:3898-3910(2010).
RN   [11]
RP   FUNCTION IN IMMUNE RESPONSE INHIBITION.
RX   PubMed=20363878; DOI=10.1210/en.2009-1498;
RA   Sun B., Qi N., Shang T., Wu H., Deng T., Han D.;
RT   "Sertoli cell-initiated testicular innate immune response through
RT   toll-like receptor-3 activation is negatively regulated by Tyro3, Axl,
RT   and mer receptors.";
RL   Endocrinology 151:2886-2897(2010).
RN   [12]
RP   INTERACTION WITH LGALS3.
RX   PubMed=21792939; DOI=10.1002/jcp.22955;
RA   Caberoy N.B., Alvarado G., Bigcas J.L., Li W.;
RT   "Galectin-3 is a new MerTK-specific eat-me signal.";
RL   J. Cell. Physiol. 227:401-407(2012).
CC   -!- FUNCTION: Receptor tyrosine kinase that transduces signals from
CC       the extracellular matrix into the cytoplasm by binding to several
CC       ligands including LGALS3, TUB, TULP1 or GAS6. Regulates many
CC       physiological processes including cell survival, migration,
CC       differentiation, and phagocytosis of apoptotic cells
CC       (efferocytosis). Ligand binding at the cell surface induces
CC       autophosphorylation of MERTK on its intracellular domain that
CC       provides docking sites for downstream signaling molecules.
CC       Following activation by ligand, interacts with GRB2 or PLCG2 and
CC       induces phosphorylation of MAPK1, MAPK2, FAK/PTK2 or RAC1. MERTK
CC       signaling plays a role in various processes such as macrophage
CC       clearance of apoptotic cells, platelet aggregation, cytoskeleton
CC       reorganization and engulfment. Functions in the retinal pigment
CC       epithelium (RPE) as a regulator of rod outer segments fragments
CC       phagocytosis. Plays also an important role in inhibition of Toll-
CC       like receptors (TLRs)-mediated innate immune response by
CC       activating STAT1, which selectively induces production of
CC       suppressors of cytokine signaling SOCS1 and SOCS3.
CC       {ECO:0000269|PubMed:19117932, ECO:0000269|PubMed:20363878}.
CC   -!- CATALYTIC ACTIVITY: ATP + a [protein]-L-tyrosine = ADP + a
CC       [protein]-L-tyrosine phosphate. {ECO:0000255|PROSITE-
CC       ProRule:PRU10028}.
CC   -!- SUBUNIT: Interacts (upon activation) with TNK2; stimulates TNK2
CC       autophosphorylation. Interacts (via N-terminus) with extracellular
CC       ligands LGALS3, TUB, TULP1 and GAS6. Interacts with VAV1 in a
CC       phosphotyrosine-independent manner (By similarity). {ECO:0000250}.
CC   -!- SUBCELLULAR LOCATION: Membrane {ECO:0000250}; Single-pass type I
CC       membrane protein {ECO:0000250}.
CC   -!- TISSUE SPECIFICITY: Expressed predominantly in the hematopoietic
CC       lineages: macrophages, NK cells, NKT cells, dendritic cells and
CC       platelets. {ECO:0000269|PubMed:12884290}.
CC   -!- DEVELOPMENTAL STAGE: Expressed during most, if not all, stages of
CC       embryological development beginning in the morula and blastocyst
CC       and progressing through the yolk sac and fetal liver stages.
CC   -!- PTM: Autophosphorylated on Tyr-744, Tyr-748 and Tyr-749 in the
CC       activation loop allowing full activity (By similarity).
CC       Autophosphorylated on Tyr-867 leading to recruitment of downstream
CC       partners of the signaling cascade such as PLCG2. {ECO:0000250,
CC       ECO:0000269|PubMed:18039660}.
CC   -!- DISRUPTION PHENOTYPE: knockout mice are fertile, but male animals
CC       that lack all three receptors TYRO3, AXL and MERTK produce no
CC       mature sperm. {ECO:0000269|PubMed:10227296}.
CC   -!- SIMILARITY: Belongs to the protein kinase superfamily. Tyr protein
CC       kinase family. AXL/UFO subfamily. {ECO:0000255|PROSITE-
CC       ProRule:PRU00159}.
CC   -!- SIMILARITY: Contains 2 fibronectin type-III domains.
CC       {ECO:0000255|PROSITE-ProRule:PRU00316}.
CC   -!- SIMILARITY: Contains 2 Ig-like C2-type (immunoglobulin-like)
CC       domains. {ECO:0000305}.
CC   -!- SIMILARITY: Contains 1 protein kinase domain.
CC       {ECO:0000255|PROSITE-ProRule:PRU00159}.
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DR   EMBL; U21301; AAA80222.1; -; mRNA.
DR   EMBL; L11625; AAA85355.1; -; mRNA.
DR   CCDS; CCDS16716.1; -.
DR   PIR; I49276; I49276.
DR   RefSeq; NP_032613.1; NM_008587.1.
DR   UniGene; Mm.239655; -.
DR   ProteinModelPortal; Q60805; -.
DR   SMR; Q60805; 97-276, 287-487, 533-863.
DR   IntAct; Q60805; 1.
DR   STRING; 10090.ENSMUSP00000014505; -.
DR   PhosphoSite; Q60805; -.
DR   MaxQB; Q60805; -.
DR   PaxDb; Q60805; -.
DR   PRIDE; Q60805; -.
DR   DNASU; 17289; -.
DR   Ensembl; ENSMUST00000014505; ENSMUSP00000014505; ENSMUSG00000014361.
DR   GeneID; 17289; -.
DR   KEGG; mmu:17289; -.
DR   UCSC; uc008mgt.1; mouse.
DR   CTD; 10461; -.
DR   MGI; MGI:96965; Mertk.
DR   eggNOG; COG0515; -.
DR   GeneTree; ENSGT00720000108377; -.
DR   HOGENOM; HOG000231685; -.
DR   HOVERGEN; HBG006346; -.
DR   InParanoid; Q60805; -.
DR   KO; K05117; -.
DR   OMA; NEIGWSA; -.
DR   OrthoDB; EOG77DJ5C; -.
DR   PhylomeDB; Q60805; -.
DR   TreeFam; TF317402; -.
DR   BRENDA; 2.7.10.1; 3474.
DR   Reactome; REACT_225233; Cell surface interactions at the vascular wall.
DR   NextBio; 291808; -.
DR   PRO; PR:Q60805; -.
DR   ArrayExpress; Q60805; -.
DR   Bgee; Q60805; -.
DR   CleanEx; MM_MERTK; -.
DR   Genevestigator; Q60805; -.
DR   GO; GO:0005737; C:cytoplasm; IEA:Ensembl.
DR   GO; GO:0005615; C:extracellular space; IEA:Ensembl.
DR   GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR   GO; GO:0001750; C:photoreceptor outer segment; IEA:Ensembl.
DR   GO; GO:0016028; C:rhabdomere; IEA:Ensembl.
DR   GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR   GO; GO:0004714; F:transmembrane receptor protein tyrosine kinase activity; IEA:UniProtKB-EC.
DR   GO; GO:0043277; P:apoptotic cell clearance; IMP:UniProtKB.
DR   GO; GO:0001779; P:natural killer cell differentiation; IGI:MGI.
DR   GO; GO:0051250; P:negative regulation of lymphocyte activation; IGI:MGI.
DR   GO; GO:0030168; P:platelet activation; IMP:MGI.
DR   GO; GO:0050766; P:positive regulation of phagocytosis; IEA:Ensembl.
DR   GO; GO:0043491; P:protein kinase B signaling; IGI:MGI.
DR   GO; GO:0060041; P:retina development in camera-type eye; IMP:MGI.
DR   GO; GO:0032940; P:secretion by cell; IMP:MGI.
DR   GO; GO:0007283; P:spermatogenesis; IGI:MGI.
DR   GO; GO:0034446; P:substrate adhesion-dependent cell spreading; IMP:MGI.
DR   GO; GO:0060068; P:vagina development; IGI:MGI.
DR   Gene3D; 2.60.40.10; -; 4.
DR   InterPro; IPR003961; Fibronectin_type3.
DR   InterPro; IPR007110; Ig-like_dom.
DR   InterPro; IPR013783; Ig-like_fold.
DR   InterPro; IPR003599; Ig_sub.
DR   InterPro; IPR011009; Kinase-like_dom.
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   Pfam; PF00041; fn3; 1.
DR   Pfam; PF07714; Pkinase_Tyr; 1.
DR   PRINTS; PR00109; TYRKINASE.
DR   SMART; SM00060; FN3; 2.
DR   SMART; SM00409; IG; 2.
DR   SMART; SM00219; TyrKc; 1.
DR   SUPFAM; SSF49265; SSF49265; 1.
DR   SUPFAM; SSF56112; SSF56112; 1.
DR   PROSITE; PS50853; FN3; 2.
DR   PROSITE; PS50835; IG_LIKE; 2.
DR   PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR   PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR   PROSITE; PS00109; PROTEIN_KINASE_TYR; 1.
PE   1: Evidence at protein level;
KW   ATP-binding; Complete proteome; Disulfide bond; Glycoprotein;
KW   Immunoglobulin domain; Kinase; Membrane; Nucleotide-binding;
KW   Phosphoprotein; Proto-oncogene; Receptor; Reference proteome; Repeat;
KW   Signal; Transferase; Transmembrane; Transmembrane helix;
KW   Tyrosine-protein kinase.
FT   SIGNAL        1     18       {ECO:0000255}.
FT   CHAIN        19    994       Tyrosine-protein kinase Mer.
FT                                /FTId=PRO_0000024444.
FT   TOPO_DOM     19    497       Extracellular. {ECO:0000255}.
FT   TRANSMEM    498    518       Helical. {ECO:0000255}.
FT   TOPO_DOM    519    994       Cytoplasmic. {ECO:0000255}.
FT   DOMAIN       75    181       Ig-like C2-type 1.
FT   DOMAIN      192    268       Ig-like C2-type 2.
FT   DOMAIN      281    376       Fibronectin type-III 1.
FT                                {ECO:0000255|PROSITE-ProRule:PRU00316}.
FT   DOMAIN      381    478       Fibronectin type-III 2.
FT                                {ECO:0000255|PROSITE-ProRule:PRU00316}.
FT   DOMAIN      582    852       Protein kinase. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00159}.
FT   NP_BIND     588    596       ATP. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00159}.
FT   ACT_SITE    718    718       Proton acceptor. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00159, ECO:0000255|PROSITE-
FT                                ProRule:PRU10028}.
FT   BINDING     610    610       ATP. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00159}.
FT   MOD_RES     538    538       Phosphoserine. {ECO:0000250}.
FT   MOD_RES     744    744       Phosphotyrosine; by autocatalysis.
FT                                {ECO:0000250}.
FT   MOD_RES     748    748       Phosphotyrosine; by autocatalysis.
FT                                {ECO:0000250}.
FT   MOD_RES     749    749       Phosphotyrosine; by autocatalysis.
FT                                {ECO:0000250}.
FT   MOD_RES     867    867       Phosphotyrosine; by autocatalysis.
FT                                {ECO:0000269|PubMed:18039660}.
FT   CARBOHYD     91     91       N-linked (GlcNAc...). {ECO:0000255}.
FT   CARBOHYD    108    108       N-linked (GlcNAc...). {ECO:0000255}.
FT   CARBOHYD    165    165       N-linked (GlcNAc...). {ECO:0000255}.
FT   CARBOHYD    202    202       N-linked (GlcNAc...). {ECO:0000255}.
FT   CARBOHYD    210    210       N-linked (GlcNAc...). {ECO:0000255}.
FT   CARBOHYD    229    229       N-linked (GlcNAc...). {ECO:0000255}.
FT   CARBOHYD    289    289       N-linked (GlcNAc...). {ECO:0000255}.
FT   CARBOHYD    311    311       N-linked (GlcNAc...). {ECO:0000255}.
FT   CARBOHYD    324    324       N-linked (GlcNAc...). {ECO:0000255}.
FT   CARBOHYD    331    331       N-linked (GlcNAc...). {ECO:0000255}.
FT   CARBOHYD    349    349       N-linked (GlcNAc...). {ECO:0000255}.
FT   CARBOHYD    384    384       N-linked (GlcNAc...). {ECO:0000255}.
FT   CARBOHYD    390    390       N-linked (GlcNAc...). {ECO:0000255}.
FT   CARBOHYD    437    437       N-linked (GlcNAc...). {ECO:0000255}.
FT   CARBOHYD    449    449       N-linked (GlcNAc...). {ECO:0000255}.
FT   DISULFID    109    170       {ECO:0000255|PROSITE-ProRule:PRU00114}.
FT   DISULFID    213    257       {ECO:0000255|PROSITE-ProRule:PRU00114}.
FT   MUTAGEN     867    867       Y->F: Loss of GRB2 binding.
FT                                {ECO:0000269|PubMed:9891051}.
FT   CONFLICT    473    476       IIIP -> SARA (in Ref. 2). {ECO:0000305}.
FT   CONFLICT    516    516       I -> V (in Ref. 2; AAA85355).
FT                                {ECO:0000305}.
SQ   SEQUENCE   994 AA;  110157 MW;  603C09FA11F76FE0 CRC64;
     MVLAPLLLGL LLLPALWSGG TAEKWEETEL DQLFSGPLPG RLPVNHRPFS APHSSRDQLP
     PPQTGRSHPA HTAAPQVTST ASKLLPPVAF NHTIGHIVLS EHKNVKFNCS INIPNTYQET
     AGISWWKDGK ELLGAHHSIT QFYPDEEGVS IIALFSIASV QRSDNGSYFC KMKVNNREIV
     SDPIYVEVQG LPYFIKQPES VNVTRNTAFN LTCQAVGPPE PVNIFWVQNS SRVNEKPERS
     PSVLTVPGLT ETAVFSCEAH NDKGLTVSKG VHINIKVIPS PPTEVHILNS TAHSILVSWV
     PGFDGYSPLQ NCSIQVKEAD RLSNGSVMVF NTSASPHLYE IQQLQALANY SIAVSCRNEI
     GWSAVSPWIL ASTTEGAPSV APLNITVFLN ESNNILDIRW TKPPIKRQDG ELVGYRISHV
     WESAGTYKEL SEEVSQNGSW AQIPVQIHNA TCTVRIAAIT KGGIGPFSEP VNIIIPEHSK
     VDYAPSSTPA PGNTDSMFII LGCFCGFILI GLILCISLAL RRRVQETKFG GAFSEEDSQL
     VVNYRAKKSF CRRAIELTLQ SLGVSEELQN KLEDVVIDRN LLVLGKVLGE GEFGSVMEGN
     LKQEDGTSQK VAVKTMKLDN FSQREIEEFL SEAACMKDFN HPNVIRLLGV CIELSSQGIP
     KPMVILPFMK YGDLHTFLLY SRLNTGPKYI HLQTLLKFMM DIAQGMEYLS NRNFLHRDLA
     ARNCMLRDDM TVCVADFGLS KKIYSGDYYR QGRIAKMPVK WIAIESLADR VYTSKSDVWA
     FGVTMWEITT RGMTPYPGVQ NHEMYDYLLH GHRLKQPEDC LDELYDIMYS CWSADPLDRP
     TFSVLRLQLE KLSESLPDAQ DKESIIYINT QLLESCEGIA NGPSLTGLDM NIDPDSIIAS
     CTPGAAVSVV TAEVHENNLR EERYILNGGN EEWEDVSSTP FAAVTPEKDG VLPEDRLTKN
     GVSWSHHSTL PLGSPSPDEL LFVDDSLEDS EVLM
//
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