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 29-MAY-2013, entry version 130.
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 AUTOPHOSPHORYLATION.
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 -!- CATALYTIC ACTIVITY: ATP + a [protein]-L-tyrosine = ADP + a
CC [protein]-L-tyrosine phosphate.
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).
CC -!- SUBCELLULAR LOCATION: Membrane; Single-pass type I membrane
CC protein (By similarity).
CC -!- TISSUE SPECIFICITY: Expressed predominantly in the hematopoietic
CC lineages: macrophages, NK cells, NKT cells, dendritic cells and
CC platelets.
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.
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.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Tyr protein
CC kinase family. AXL/UFO subfamily.
CC -!- SIMILARITY: Contains 2 fibronectin type-III domains.
CC -!- SIMILARITY: Contains 2 Ig-like C2-type (immunoglobulin-like)
CC domains.
CC -!- SIMILARITY: Contains 1 protein kinase domain.
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DR EMBL; U21301; AAA80222.1; -; mRNA.
DR EMBL; L11625; AAA85355.1; -; mRNA.
DR IPI; IPI00121254; -.
DR PIR; I49276; I49276.
DR RefSeq; NP_032613.1; NM_008587.1.
DR UniGene; Mm.239655; -.
DR ProteinModelPortal; Q60805; -.
DR SMR; Q60805; 97-276, 361-487, 533-895.
DR IntAct; Q60805; 1.
DR STRING; 10090.ENSMUSP00000014505; -.
DR PhosphoSite; 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; ENSGT00550000074361; -.
DR HOGENOM; HOG000231685; -.
DR HOVERGEN; HBG006346; -.
DR InParanoid; Q60805; -.
DR KO; K05117; -.
DR OMA; TGPKHIP; -.
DR OrthoDB; EOG4Z8XW3; -.
DR BRENDA; 2.7.10.1; 3474.
DR NextBio; 291808; -.
DR ArrayExpress; Q60805; -.
DR Bgee; Q60805; -.
DR CleanEx; MM_MERTK; -.
DR Genevestigator; Q60805; -.
DR GermOnline; ENSMUSG00000014361; Mus musculus.
DR GO; GO:0005737; C:cytoplasm; IEA:Compara.
DR GO; GO:0005615; C:extracellular space; IEA:Compara.
DR GO; GO:0016021; C:integral to membrane; IEA:UniProtKB-KW.
DR GO; GO:0001750; C:photoreceptor outer segment; IEA:Compara.
DR GO; GO:0016028; C:rhabdomere; IEA:Compara.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0004714; F:transmembrane receptor protein tyrosine kinase activity; IEA: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:Compara.
DR GO; GO:0043491; P:protein kinase B signaling cascade; 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_cat_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; FN_III-like; 2.
DR SUPFAM; SSF56112; Kinase_like; 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 Potential.
FT CHAIN 19 994 Tyrosine-protein kinase Mer.
FT /FTId=PRO_0000024444.
FT TOPO_DOM 19 497 Extracellular (Potential).
FT TRANSMEM 498 518 Helical; (Potential).
FT TOPO_DOM 519 994 Cytoplasmic (Potential).
FT DOMAIN 75 181 Ig-like C2-type 1.
FT DOMAIN 192 268 Ig-like C2-type 2.
FT DOMAIN 279 374 Fibronectin type-III 1.
FT DOMAIN 378 477 Fibronectin type-III 2.
FT DOMAIN 582 852 Protein kinase.
FT NP_BIND 588 596 ATP (By similarity).
FT ACT_SITE 718 718 Proton acceptor (By similarity).
FT BINDING 610 610 ATP (By similarity).
FT MOD_RES 538 538 Phosphoserine (By similarity).
FT MOD_RES 744 744 Phosphotyrosine; by autocatalysis (By
FT similarity).
FT MOD_RES 748 748 Phosphotyrosine; by autocatalysis (By
FT similarity).
FT MOD_RES 749 749 Phosphotyrosine; by autocatalysis (By
FT similarity).
FT MOD_RES 867 867 Phosphotyrosine; by autocatalysis.
FT CARBOHYD 91 91 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 108 108 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 165 165 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 202 202 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 210 210 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 229 229 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 289 289 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 311 311 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 324 324 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 331 331 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 349 349 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 384 384 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 390 390 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 437 437 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 449 449 N-linked (GlcNAc...) (Potential).
FT DISULFID 109 170 By similarity.
FT DISULFID 213 257 By similarity.
FT MUTAGEN 867 867 Y->F: Loss of GRB2 binding.
FT CONFLICT 473 476 IIIP -> SARA (in Ref. 2).
FT CONFLICT 516 516 I -> V (in Ref. 2; AAA85355).
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
//
