FGR_RAT
ID FGR_RAT Reviewed; 517 AA.
AC Q6P6U0; Q63206;
DT 19-OCT-2011, integrated into UniProtKB/Swiss-Prot.
DT 05-JUL-2004, sequence version 1.
DT 03-AUG-2022, entry version 149.
DE RecName: Full=Tyrosine-protein kinase Fgr;
DE EC=2.7.10.2;
DE AltName: Full=Proto-oncogene c-Fgr;
DE AltName: Full=p55-Fgr;
GN Name=Fgr;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC STRAIN=Fischer 344; TISSUE=Leukemia;
RA Yue C.C., Labash J.D., Jaye M.;
RT "Nucleotide and deduced amino acid sequence of rat FGR.";
RL Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Brown Norway;
RA Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Prostate;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP PARTIAL PROTEIN SEQUENCE, CATALYTIC ACTIVITY, PHOSPHORYLATION AT TYR-400
RP AND TYR-511, IDENTIFICATION BY MASS SPECTROMETRY, AND ACTIVITY REGULATION.
RX PubMed=7515063; DOI=10.1016/s0021-9258(17)40763-0;
RA Ruzzene M., James P., Brunati A.M., Donella-Deana A., Pinna L.A.;
RT "Regulation of c-Fgr protein kinase by c-Src kinase (CSK) and by
RT polycationic effectors.";
RL J. Biol. Chem. 269:15885-15891(1994).
RN [5]
RP FUNCTION IN PHOSPHORYLATION OF HCLS1.
RX PubMed=8611520; DOI=10.1021/bi9528614;
RA Ruzzene M., Brunati A.M., Marin O., Donella-Deana A., Pinna L.A.;
RT "SH2 domains mediate the sequential phosphorylation of HS1 protein by
RT p72syk and Src-related protein tyrosine kinases.";
RL Biochemistry 35:5327-5332(1996).
RN [6]
RP FUNCTION IN PHOSPHORYLATION OF HCLS1, AUTOPHOSPHORYLATION, AND ACTIVITY
RP REGULATION.
RX PubMed=9183008; DOI=10.1111/j.1432-1033.1997.t01-1-00701.x;
RA Ruzzene M., Brunati A.M., Donella-Deana A., Marin O., Pinna L.A.;
RT "Specific stimulation of c-Fgr kinase by tyrosine-phosphorylated
RT (poly)peptides--possible implication in the sequential mode of protein
RT phosphorylation.";
RL Eur. J. Biochem. 245:701-707(1997).
RN [7]
RP CATALYTIC ACTIVITY, FUNCTION IN PHOSPHORYLATION OF HCLS1, INTERACTION WITH
RP HCLS1, AND AUTOPHOSPHORYLATION.
RX PubMed=10066823; DOI=10.1074/jbc.274.11.7557;
RA Brunati A.M., Donella-Deana A., James P., Quadroni M., Contri A., Marin O.,
RA Pinna L.A.;
RT "Molecular features underlying the sequential phosphorylation of HS1
RT protein and its association with c-Fgr protein-tyrosine kinase.";
RL J. Biol. Chem. 274:7557-7564(1999).
RN [8]
RP FUNCTION IN PHOSPHORYLATION OF PLD2 AND MAST CELL ACTIVATION, AND
RP INTERACTION WITH PLD2.
RX PubMed=15282299; DOI=10.1128/mcb.24.16.6980-6992.2004;
RA Choi W.S., Hiragun T., Lee J.H., Kim Y.M., Kim H.P., Chahdi A., Her E.,
RA Han J.W., Beaven M.A.;
RT "Activation of RBL-2H3 mast cells is dependent on tyrosine phosphorylation
RT of phospholipase D2 by Fyn and Fgr.";
RL Mol. Cell. Biol. 24:6980-6992(2004).
RN [9]
RP SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=18247338; DOI=10.1002/jcb.21670;
RA Tibaldi E., Brunati A.M., Massimino M.L., Stringaro A., Colone M.,
RA Agostinelli E., Arancia G., Toninello A.;
RT "Src-Tyrosine kinases are major agents in mitochondrial tyrosine
RT phosphorylation.";
RL J. Cell. Biochem. 104:840-849(2008).
RN [10]
RP FUNCTION IN MAST CELL DEGRANULATION AND PHOSPHORYLATION OF SYK, INTERACTION
RP WITH MS4A2/FCER1B, AND SUBCELLULAR LOCATION ON PLASMA MEMBRANE LIPID RAFTS.
RX PubMed=21746961; DOI=10.4049/jimmunol.1100296;
RA Lee J.H., Kim J.W., Kim do K., Kim H.S., Park H.J., Park D.K., Kim A.R.,
RA Kim B., Beaven M.A., Park K.L., Kim Y.M., Choi W.S.;
RT "The Src family kinase Fgr is critical for activation of mast cells and
RT IgE-mediated anaphylaxis in mice.";
RL J. Immunol. 187:1807-1815(2011).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-50, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22673903; DOI=10.1038/ncomms1871;
RA Lundby A., Secher A., Lage K., Nordsborg N.B., Dmytriyev A., Lundby C.,
RA Olsen J.V.;
RT "Quantitative maps of protein phosphorylation sites across 14 different rat
RT organs and tissues.";
RL Nat. Commun. 3:876-876(2012).
CC -!- FUNCTION: Non-receptor tyrosine-protein kinase that transmits signals
CC from cell surface receptors devoid of kinase activity and contributes
CC to the regulation of immune responses, including neutrophil, monocyte,
CC macrophage and mast cell functions, cytoskeleton remodeling in response
CC to extracellular stimuli, phagocytosis, cell adhesion and migration.
CC Promotes mast cell degranulation, release of inflammatory cytokines and
CC IgE-mediated anaphylaxis. Acts downstream of receptors that bind the Fc
CC region of immunoglobulins, such as MS4A2/FCER1B, FCER1G and FCGR2. Acts
CC downstream of ITGB1 and ITGB2, and regulates actin cytoskeleton
CC reorganization, cell spreading and adhesion. Depending on the context,
CC activates or inhibits cellular responses. Functions as negative
CC regulator of ITGB2 signaling, phagocytosis and SYK activity in
CC monocytes. Required for normal ITGB1 and ITGB2 signaling, normal cell
CC spreading and adhesion in neutrophils and macrophages. Functions as
CC positive regulator of cell migration and regulates cytoskeleton
CC reorganization via RAC1 activation. Phosphorylates SYK (in vitro) and
CC promotes SYK-dependent activation of AKT1 and MAP kinase signaling.
CC Phosphorylates PLD2 in antigen-stimulated mast cells, leading to PLD2
CC activation and the production of the signaling molecules
CC lysophosphatidic acid and diacylglycerol. Promotes activation of
CC PIK3R1. Phosphorylates FASLG, and thereby regulates its ubiquitination
CC and subsequent internalization. Phosphorylates ABL1. Promotes
CC phosphorylation of CBL, CTTN, PIK3R1, PTK2/FAK1, PTK2B/PYK2 and VAV2
CC (By similarity). Phosphorylates HCLS1 that has already been
CC phosphorylated by SYK, but not unphosphorylated HCLS1. Together with
CC CLNK, it acts as a negative regulator of natural killer cell-activating
CC receptors and inhibits interferon-gamma production (By similarity).
CC {ECO:0000250, ECO:0000250|UniProtKB:P14234,
CC ECO:0000269|PubMed:10066823, ECO:0000269|PubMed:15282299,
CC ECO:0000269|PubMed:21746961, ECO:0000269|PubMed:8611520,
CC ECO:0000269|PubMed:9183008}.
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 ECO:0000269|PubMed:10066823, ECO:0000269|PubMed:7515063};
CC -!- ACTIVITY REGULATION: Activated by autophosphorylation. Prior
CC phosphorylation at Tyr-511 by SRC inhibits ulterior autophosphorylation
CC at Tyr-400. Activated by phorbol myristate acetate, phosphatidic acid
CC and poly-Lys. Binding (via SH2 domain) of HCLS1 that is already
CC phosphorylated by SYK strongly increases kinase activity.
CC {ECO:0000269|PubMed:7515063, ECO:0000269|PubMed:9183008}.
CC -!- SUBUNIT: Interacts with ITGB1, ITGB2, MS4A2/FCER1B and FCGR2. Interacts
CC (via SH2 domain) with SYK (tyrosine phosphorylated). Interacts (via SH2
CC domain) with FLT3 (tyrosine phosphorylated). Interacts with PTK2/FAK1.
CC Interacts (via SH2 domain) with HCLS1 (tyrosine phosphorylated by SYK).
CC Interacts with SIRPA and PTPNS1. Interacts (not phosphorylated on
CC tyrosine residues) with CBL; FGR tyrosine phosphorylation promotes
CC dissociation (By similarity). Interacts with CLNK (By similarity).
CC {ECO:0000250, ECO:0000250|UniProtKB:P14234}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000305}; Lipid-anchor
CC {ECO:0000305}; Cytoplasmic side {ECO:0000305}. Cell membrane;
CC Peripheral membrane protein; Cytoplasmic side. Cell projection, ruffle
CC membrane {ECO:0000250}. Cytoplasm, cytosol {ECO:0000250}. Cytoplasm,
CC cytoskeleton {ECO:0000250}. Mitochondrion inner membrane. Mitochondrion
CC intermembrane space. Note=Colocalizes with actin fibers at membrane
CC ruffles (By similarity). Detected at plasma membrane lipid rafts.
CC Detected in mitochondrial intermembrane space and at inner membranes.
CC {ECO:0000250}.
CC -!- TISSUE SPECIFICITY: Detected in brain cortex (at protein level).
CC {ECO:0000269|PubMed:18247338}.
CC -!- PTM: Ubiquitinated. Becomes ubiquitinated in response to ITGB2
CC signaling; this does not lead to degradation (By similarity).
CC {ECO:0000250}.
CC -!- PTM: Phosphorylated. Autophosphorylated on tyrosine residues. Becomes
CC phosphorylated in response to FCGR2 engagement, cell adhesion and
CC signaling by ITGB2 (By similarity). Prior phosphorylation at Tyr-511 by
CC SRC inhibits ulterior autophosphorylation at Tyr-400. {ECO:0000250,
CC ECO:0000269|PubMed:7515063}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Tyr protein
CC kinase family. SRC subfamily. {ECO:0000255|PROSITE-ProRule:PRU00159}.
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DR EMBL; X57018; CAA40337.1; -; mRNA.
DR EMBL; CH473968; EDL80655.1; -; Genomic_DNA.
DR EMBL; CH473968; EDL80656.1; -; Genomic_DNA.
DR EMBL; CH473968; EDL80657.1; -; Genomic_DNA.
DR EMBL; BC062025; AAH62025.1; -; mRNA.
DR PIR; S24547; S24547.
DR RefSeq; NP_077059.2; NM_024145.2.
DR RefSeq; XP_006239141.1; XM_006239079.3.
DR RefSeq; XP_006239142.1; XM_006239080.3.
DR RefSeq; XP_006239143.1; XM_006239081.3.
DR RefSeq; XP_006239144.1; XM_006239082.3.
DR AlphaFoldDB; Q6P6U0; -.
DR SMR; Q6P6U0; -.
DR BioGRID; 249398; 2.
DR IntAct; Q6P6U0; 2.
DR MINT; Q6P6U0; -.
DR STRING; 10116.ENSRNOP00000013779; -.
DR BindingDB; Q6P6U0; -.
DR ChEMBL; CHEMBL4362; -.
DR iPTMnet; Q6P6U0; -.
DR PhosphoSitePlus; Q6P6U0; -.
DR jPOST; Q6P6U0; -.
DR PaxDb; Q6P6U0; -.
DR PRIDE; Q6P6U0; -.
DR Ensembl; ENSRNOT00000013778; ENSRNOP00000013779; ENSRNOG00000009912.
DR GeneID; 79113; -.
DR KEGG; rno:79113; -.
DR UCSC; RGD:621319; rat.
DR CTD; 2268; -.
DR RGD; 621319; Fgr.
DR eggNOG; KOG0197; Eukaryota.
DR GeneTree; ENSGT00940000157554; -.
DR HOGENOM; CLU_000288_7_2_1; -.
DR InParanoid; Q6P6U0; -.
DR OMA; AQIPNYN; -.
DR OrthoDB; 539311at2759; -.
DR PhylomeDB; Q6P6U0; -.
DR TreeFam; TF351634; -.
DR Reactome; R-RNO-2029481; FCGR activation.
DR Reactome; R-RNO-432142; Platelet sensitization by LDL.
DR Reactome; R-RNO-6798695; Neutrophil degranulation.
DR PRO; PR:Q6P6U0; -.
DR Proteomes; UP000002494; Chromosome 5.
DR Proteomes; UP000234681; Chromosome 5.
DR Bgee; ENSRNOG00000009912; Expressed in spleen and 19 other tissues.
DR Genevisible; Q6P6U0; RN.
DR GO; GO:0015629; C:actin cytoskeleton; IEA:Ensembl.
DR GO; GO:0016235; C:aggresome; IEA:Ensembl.
DR GO; GO:0005829; C:cytosol; IDA:RGD.
DR GO; GO:0031234; C:extrinsic component of cytoplasmic side of plasma membrane; IBA:GO_Central.
DR GO; GO:0005743; C:mitochondrial inner membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005758; C:mitochondrial intermembrane space; IEA:UniProtKB-SubCell.
DR GO; GO:0005886; C:plasma membrane; IDA:RGD.
DR GO; GO:0032587; C:ruffle membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0034988; F:Fc-gamma receptor I complex binding; ISO:RGD.
DR GO; GO:0034987; F:immunoglobulin receptor binding; ISS:UniProtKB.
DR GO; GO:0004715; F:non-membrane spanning protein tyrosine kinase activity; ISO:RGD.
DR GO; GO:0001784; F:phosphotyrosine residue binding; ISS:UniProtKB.
DR GO; GO:0019901; F:protein kinase binding; ISS:UniProtKB.
DR GO; GO:0004713; F:protein tyrosine kinase activity; IDA:RGD.
DR GO; GO:0005102; F:signaling receptor binding; IBA:GO_Central.
DR GO; GO:0030282; P:bone mineralization; ISO:RGD.
DR GO; GO:0030154; P:cell differentiation; IBA:GO_Central.
DR GO; GO:0050830; P:defense response to Gram-positive bacterium; ISS:UniProtKB.
DR GO; GO:0045087; P:innate immune response; IBA:GO_Central.
DR GO; GO:0007229; P:integrin-mediated signaling pathway; ISS:UniProtKB.
DR GO; GO:0032815; P:negative regulation of natural killer cell activation; ISO:RGD.
DR GO; GO:0018108; P:peptidyl-tyrosine phosphorylation; ISS:UniProtKB.
DR GO; GO:0030335; P:positive regulation of cell migration; ISS:UniProtKB.
DR GO; GO:0001819; P:positive regulation of cytokine production; ISS:UniProtKB.
DR GO; GO:0043306; P:positive regulation of mast cell degranulation; ISS:UniProtKB.
DR GO; GO:0043552; P:positive regulation of phosphatidylinositol 3-kinase activity; ISO:RGD.
DR GO; GO:0014068; P:positive regulation of phosphatidylinositol 3-kinase signaling; ISO:RGD.
DR GO; GO:0046777; P:protein autophosphorylation; ISO:RGD.
DR GO; GO:0008360; P:regulation of cell shape; ISS:UniProtKB.
DR GO; GO:0045088; P:regulation of innate immune response; ISS:UniProtKB.
DR GO; GO:0050764; P:regulation of phagocytosis; ISS:UniProtKB.
DR GO; GO:0045859; P:regulation of protein kinase activity; ISS:UniProtKB.
DR GO; GO:0048705; P:skeletal system morphogenesis; ISO:RGD.
DR GO; GO:0007169; P:transmembrane receptor protein tyrosine kinase signaling pathway; IBA:GO_Central.
DR CDD; cd10367; SH2_Src_Fgr; 1.
DR Gene3D; 3.30.505.10; -; 1.
DR InterPro; IPR035693; Fgr_SH2.
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; 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; Cell projection; Cytoplasm; Cytoskeleton;
KW Direct protein sequencing; Immunity; Innate immunity; Kinase; Lipoprotein;
KW Membrane; Mitochondrion; Mitochondrion inner membrane; Myristate;
KW Nucleotide-binding; Palmitate; Phosphoprotein; Proto-oncogene;
KW Reference proteome; SH3 domain; Transferase; Tyrosine-protein kinase;
KW Ubl conjugation.
FT INIT_MET 1
FT /note="Removed"
FT CHAIN 2..517
FT /note="Tyrosine-protein kinase Fgr"
FT /id="PRO_0000413581"
FT DOMAIN 65..126
FT /note="SH3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00192"
FT DOMAIN 132..229
FT /note="SH2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00191"
FT DOMAIN 251..504
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 17..46
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 370
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10028"
FT BINDING 257..265
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 279
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 32
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:P09769"
FT MOD_RES 50
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 196
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:P14234"
FT MOD_RES 206
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P14234"
FT MOD_RES 400
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000269|PubMed:7515063"
FT MOD_RES 511
FT /note="Phosphotyrosine; by SRC"
FT /evidence="ECO:0000269|PubMed:7515063"
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 6
FT /note="S-palmitoyl cysteine"
FT /evidence="ECO:0000250"
FT CONFLICT 313
FT /note="V -> A (in Ref. 1; CAA40337)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 517 AA; 58821 MW; 0D960BBBCAF2911B CRC64;
MGCVFCKKLE PAPKEDVGLE GDFRSQGAEE RYYPDPTQGR SSSISPQPIS PAFLNVGNIR
SVSGTGVTIF VALYDYEART GDDLTFTKGE KFHILNNTEY DWWEARSLSS GRTGYVPSNY
VAPVDSIQAE EWYFGKISRK DAERQLLSDG NPQGAFLIRE SETTKGAYSL SIRDWDQNRG
DHIKHYKIRK LDMGGYYITT RAQFESVQDL VRHYMEVNDG LCYLLTAPCM VMKPQTLGLA
KDAWEIDRNS IALDRRLGTG CFGDVWLGTW NCSTKVAVKT LKPGTMSPKA FLEEAQIMKL
LRHDKLVQLY AVVSEEPIYI VTEFMCYGSL LDFLKDRKGH NLMLPNLVDM AAQVAEGMAY
MERMNYIHRD LRAANILVGE HLICKIADFG LARLIVDDEY NPQQGTKFPI KWTAPEAALF
GRFTVKSDVW SFGILLTELI TKGRVPYPGM NNREVLEQVE HGYHMPCPPG CPVSLYEVME
QTWRLDPEER PTFEYLQSFL EDYFTSTEPQ YQPGDQT
