Q6P6U0 (FGR_RAT) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Tyrosine-protein kinase Fgr
EC=2.7.10.2

Alternative name(s):
Proto-oncogene c-Fgr
p55-Fgr

Gene names

Name:

Fgr

Organism

Rattus norvegicus (Rat) [Reference proteome]

Taxonomic identifier

10116 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Rattus

Protein attributes

Sequence length	517 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Non-receptor tyrosine-protein kinase that transmits signals from cell surface receptors devoid of kinase activity and contributes to the regulation of immune responses, including neutrophil, monocyte, macrophage and mast cell functions, cytoskeleton remodeling in response to extracellular stimuli, phagocytosis, cell adhesion and migration. Promotes mast cell degranulation, release of inflammatory cytokines and IgE-mediated anaphylaxis. Acts downstream of receptors that bind the Fc region of immunoglobulins, such as MS4A2/FCER1B, FCER1G and FCGR2. Acts downstream of ITGB1 and ITGB2, and regulates actin cytoskeleton reorganization, cell spreading and adhesion. Depending on the context, activates or inhibits cellular responses. Functions as negative regulator of ITGB2 signaling, phagocytosis and SYK activity in monocytes. Required for normal ITGB1 and ITGB2 signaling, normal cell spreading and adhesion in neutrophils and macrophages. Functions as positive regulator of cell migration and regulates cytoskeleton reorganization via RAC1 activation. Phosphorylates SYK (in vitro) and promotes SYK-dependent activation of AKT1 and MAP kinase signaling. Phosphorylates PLD2 in antigen-stimulated mast cells, leading to PLD2 activation and the production of the signaling molecules lysophosphatidic acid and diacylglycerol. Promotes activation of PIK3R1. Phosphorylates FASLG, and thereby regulates its ubiquitination and subsequent internalization. Phosphorylates ABL1. Promotes phosphorylation of CBL, CTTN, PIK3R1, PTK2/FAK1, PTK2B/PYK2 and VAV2 By similarity. Phosphorylates HCLS1 that has already been phosphorylated by SYK, but not unphosphorylated HCLS1. Ref.5 Ref.6 Ref.7 Ref.8 Ref.10
Catalytic activity	ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate. Ref.4 Ref.7
Enzyme regulation	Activated by autophosphorylation. Prior phosphorylation at Tyr-511 by SRC inhibits ulterior autophosphorylation at Tyr-400. Activated by phorbol myristate acetate, phosphatidic acid and poly-Lys. Binding (via SH2 domain) of HCLS1 that is already phosphorylated by SYK strongly increases kinase activity. Ref.4 Ref.6
Subunit structure	Interacts with ITGB1, ITGB2, MS4A2/FCER1B and FCGR2. Interacts (via SH2 domain) with SYK (tyrosine phosphorylated). Interacts (via SH2 domain) with FLT3 (tyrosine phosphorylated). Interacts with PTK2/FAK1. Interacts (via SH2 domain) with HCLS1 (tyrosine phosphorylated by SYK). Interacts with SIRPA and PTPNS1. Interacts (not phosphorylated on tyrosine residues) with CBL; FGR tyrosine phosphorylation promotes dissociation By similarity. Ref.7 Ref.8 Ref.10
Subcellular location	Cell membrane; Lipid-anchor; Cytoplasmic side Probable. Cell membrane; Peripheral membrane protein; Cytoplasmic side. Cell projection › ruffle membrane By similarity. Cytoplasm › cytosol By similarity. Cytoplasm › cytoskeleton By similarity. Mitochondrion inner membrane. Mitochondrion intermembrane space. Note: Colocalizes with actin fibers at membrane ruffles By similarity. Detected at plasma membrane lipid rafts. Detected in mitochondrial intermembrane space and at inner membranes. Ref.9 Ref.10
Tissue specificity	Detected in brain cortex (at protein level). Ref.9
Post-translational modification	Ubiquitinated. Becomes ubiquitinated in response to ITGB2 signaling; this does not lead to degradation By similarity. Phosphorylated. Autophosphorylated on tyrosine residues. Becomes phosphorylated in response to FCGR2 engagement, cell adhesion and signaling by ITGB2 By similarity. Prior phosphorylation at Tyr-511 by SRC inhibits ulterior autophosphorylation at Tyr-400. Ref.4 Ref.6 Ref.7
Sequence similarities	Belongs to the protein kinase superfamily. Tyr protein kinase family. SRC subfamily. Contains 1 protein kinase domain. Contains 1 SH2 domain. Contains 1 SH3 domain.

Ontologies

Keywords
Biological process	Immunity Innate immunity
Cellular component	Cell membrane Cell projection Cytoplasm Cytoskeleton Membrane Mitochondrion Mitochondrion inner membrane
Disease	Proto-oncogene
Domain	SH3 domain
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Transferase Tyrosine-protein kinase
PTM	Lipoprotein Myristate Palmitate Phosphoprotein Ubl conjugation
Technical term	Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	defense response to Gram-positive bacterium Inferred from sequence or structural similarity. Source: UniProtKB innate immune response Inferred from electronic annotation. Source: UniProtKB-KW integrin-mediated signaling pathway Inferred from sequence or structural similarity. Source: UniProtKB peptidyl-tyrosine phosphorylation Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of cell migration Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of cytokine secretion Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of mast cell degranulation Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of phosphatidylinositol 3-kinase activity Inferred from electronic annotation. Source: Compara positive regulation of phosphatidylinositol 3-kinase cascade Inferred from electronic annotation. Source: Compara protein autophosphorylation Inferred from electronic annotation. Source: Compara regulation of cell shape Inferred from sequence or structural similarity. Source: UniProtKB regulation of innate immune response Inferred from sequence or structural similarity. Source: UniProtKB regulation of phagocytosis Inferred from sequence or structural similarity. Source: UniProtKB regulation of protein kinase activity Inferred from sequence or structural similarity. Source: UniProtKB
Cellular_component	actin cytoskeleton Inferred from electronic annotation. Source: Compara cytosol Inferred from direct assay PubMed 9116282. Source: RGD mitochondrial inner membrane Inferred from electronic annotation. Source: UniProtKB-SubCell mitochondrial intermembrane space Inferred from electronic annotation. Source: UniProtKB-SubCell plasma membrane Inferred from direct assay PubMed 9116282. Source: RGD ruffle membrane Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW immunoglobulin receptor binding Inferred from sequence or structural similarity. Source: UniProtKB non-membrane spanning protein tyrosine kinase activity Inferred from electronic annotation. Source: EC phosphotyrosine binding Inferred from sequence or structural similarity. Source: UniProtKB protein kinase binding Inferred from sequence or structural similarity. Source: UniProtKB protein tyrosine kinase activity Inferred from direct assay Ref.8. Source: RGD
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Initiator methionine	1	1	Removed By similarity
	Chain	2 – 517	516	Tyrosine-protein kinase Fgr		PRO_0000413581
Regions
	Domain	65 – 126	62	SH3
	Domain	132 – 229	98	SH2
	Domain	251 – 504	254	Protein kinase
	Nucleotide binding	257 – 265	9	ATP By similarity
Sites
	Active site	370	1	Proton acceptor By similarity
	Binding site	279	1	ATP By similarity
Amino acid modifications
	Modified residue	25	1	Phosphoserine By similarity
	Modified residue	32	1	Phosphotyrosine By similarity
	Modified residue	196	1	Phosphotyrosine By similarity
	Modified residue	400	1	Phosphotyrosine; by autocatalysis Ref.4
	Modified residue	511	1	Phosphotyrosine; by SRC Ref.4
	Modified residue	517	1	Phosphothreonine By similarity
	Lipidation	2	1	N-myristoyl glycine By similarity
	Lipidation	3	1	S-palmitoyl cysteine By similarity
	Lipidation	6	1	S-palmitoyl cysteine By similarity
Experimental info
	Sequence conflict	313	1	V → A in CAA40337. Ref.1

Sequences

	Sequence		Length	Mass (Da)
	Q6P6U0 [UniParc]. Last modified July 5, 2004. Version 1. Checksum: 0D960BBBCAF2911B	FASTA	517	58,821
	10 20 30 40 50 60 MGCVFCKKLE PAPKEDVGLE GDFRSQGAEE RYYPDPTQGR SSSISPQPIS PAFLNVGNIR 70 80 90 100 110 120 SVSGTGVTIF VALYDYEART GDDLTFTKGE KFHILNNTEY DWWEARSLSS GRTGYVPSNY 130 140 150 160 170 180 VAPVDSIQAE EWYFGKISRK DAERQLLSDG NPQGAFLIRE SETTKGAYSL SIRDWDQNRG 190 200 210 220 230 240 DHIKHYKIRK LDMGGYYITT RAQFESVQDL VRHYMEVNDG LCYLLTAPCM VMKPQTLGLA 250 260 270 280 290 300 KDAWEIDRNS IALDRRLGTG CFGDVWLGTW NCSTKVAVKT LKPGTMSPKA FLEEAQIMKL 310 320 330 340 350 360 LRHDKLVQLY AVVSEEPIYI VTEFMCYGSL LDFLKDRKGH NLMLPNLVDM AAQVAEGMAY 370 380 390 400 410 420 MERMNYIHRD LRAANILVGE HLICKIADFG LARLIVDDEY NPQQGTKFPI KWTAPEAALF 430 440 450 460 470 480 GRFTVKSDVW SFGILLTELI TKGRVPYPGM NNREVLEQVE HGYHMPCPPG CPVSLYEVME 490 500 510 QTWRLDPEER PTFEYLQSFL EDYFTSTEPQ YQPGDQT

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Nucleotide and deduced amino acid sequence of rat FGR." Yue C.C., Labash J.D., Jaye M. Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Strain: Fischer 344. Tissue: Leukemia.
[2]	Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C. Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. Strain: Brown Norway.
[3]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Prostate.
[4]	"Regulation of c-Fgr protein kinase by c-Src kinase (CSK) and by polycationic effectors." Ruzzene M., James P., Brunati A.M., Donella-Deana A., Pinna L.A. J. Biol. Chem. 269:15885-15891(1994) [PubMed] [Europe PMC] [Abstract] Cited for: PARTIAL PROTEIN SEQUENCE, CATALYTIC ACTIVITY, PHOSPHORYLATION AT TYR-400 AND TYR-511, MASS SPECTROMETRY, ENZYME REGULATION.
[5]	"SH2 domains mediate the sequential phosphorylation of HS1 protein by p72syk and Src-related protein tyrosine kinases." Ruzzene M., Brunati A.M., Marin O., Donella-Deana A., Pinna L.A. Biochemistry 35:5327-5332(1996) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN PHOSPHORYLATION OF HCLS1.
[6]	"Specific stimulation of c-Fgr kinase by tyrosine-phosphorylated (poly)peptides--possible implication in the sequential mode of protein phosphorylation." Ruzzene M., Brunati A.M., Donella-Deana A., Marin O., Pinna L.A. Eur. J. Biochem. 245:701-707(1997) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN PHOSPHORYLATION OF HCLS1, AUTOPHOSPHORYLATION, ENZYME REGULATION.
[7]	"Molecular features underlying the sequential phosphorylation of HS1 protein and its association with c-Fgr protein-tyrosine kinase." Brunati A.M., Donella-Deana A., James P., Quadroni M., Contri A., Marin O., Pinna L.A. J. Biol. Chem. 274:7557-7564(1999) [PubMed] [Europe PMC] [Abstract] Cited for: CATALYTIC ACTIVITY, FUNCTION IN PHOSPHORYLATION OF HCLS1, INTERACTION WITH HCLS1, AUTOPHOSPHORYLATION.
[8]	"Activation of RBL-2H3 mast cells is dependent on tyrosine phosphorylation of phospholipase D2 by Fyn and Fgr." Choi W.S., Hiragun T., Lee J.H., Kim Y.M., Kim H.P., Chahdi A., Her E., Han J.W., Beaven M.A. Mol. Cell. Biol. 24:6980-6992(2004) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN PHOSPHORYLATION OF PLD2 AND MAST CELL ACTIVATION, INTERACTION WITH PLD2.
[9]	"Src-Tyrosine kinases are major agents in mitochondrial tyrosine phosphorylation." Tibaldi E., Brunati A.M., Massimino M.L., Stringaro A., Colone M., Agostinelli E., Arancia G., Toninello A. J. Cell. Biochem. 104:840-849(2008) [PubMed] [Europe PMC] [Abstract] Cited for: SUBCELLULAR LOCATION, TISSUE SPECIFICITY.
[10]	"The Src family kinase Fgr is critical for activation of mast cells and IgE-mediated anaphylaxis in mice." Lee J.H., Kim J.W., Kim do K., Kim H.S., Park H.J., Park D.K., Kim A.R., Kim B., Beaven M.A., Park K.L., Kim Y.M., Choi W.S. J. Immunol. 187:1807-1815(2011) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN MAST CELL DEGRANULATION AND PHOSPHORYLATION OF SYK, INTERACTION WITH MS4A2/FCER1B, SUBCELLULAR LOCATION ON PLASMA MEMBRANE LIPID RAFTS.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	X57018 mRNA. Translation: CAA40337.1. CH473968 Genomic DNA. Translation: EDL80655.1. CH473968 Genomic DNA. Translation: EDL80656.1. CH473968 Genomic DNA. Translation: EDL80657.1. BC062025 mRNA. Translation: AAH62025.1.
IPI	IPI00471744.
PIR	S24547.
RefSeq	NP_077059.2. NM_024145.2.
UniGene	Rn.11309.
3D structure databases
HSSP	HSSP built from PDB template 1A0N based on UniProtKB P06241.
ProteinModelPortal	Q6P6U0.
SMR	Q6P6U0. Positions 67-515.
ModBase	Search...
Protein-protein interaction databases
STRING	10116.ENSRNOP00000013779.
PTM databases
PhosphoSite	Q6P6U0.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSRNOT00000013778; ENSRNOP00000013779; ENSRNOG00000009912.
GeneID	79113.
KEGG	rno:79113.
UCSC	RGD:621319. rat.
Organism-specific databases
CTD	2268.
RGD	621319. Fgr.
Phylogenomic databases
eggNOG	COG0515.
GeneTree	ENSGT00620000087702.
HOGENOM	HOG000233858.
HOVERGEN	HBG008761.
InParanoid	Q6P6U0.
KO	K08891.
OMA	RGDHVKH.
OrthoDB	EOG4GMTWM.
Gene expression databases
Genevestigator	Q6P6U0.
Family and domain databases
Gene3D	3.30.505.10. 1 hit.
InterPro	IPR011009. Kinase-like_dom. IPR000719. Prot_kinase_cat_dom. IPR017441. Protein_kinase_ATP_BS. IPR001245. Ser-Thr/Tyr_kinase_cat_dom. IPR000980. SH2. IPR001452. SH3_domain. IPR008266. Tyr_kinase_AS. IPR020635. Tyr_kinase_cat_dom. [Graphical view]
Pfam	PF07714. Pkinase_Tyr. 1 hit. PF00017. SH2. 1 hit. PF00018. SH3_1. 1 hit. [Graphical view]
PRINTS	PR00401. SH2DOMAIN. PR00452. SH3DOMAIN. PR00109. TYRKINASE.
SMART	SM00252. SH2. 1 hit. SM00326. SH3. 1 hit. SM00219. TyrKc. 1 hit. [Graphical view]
SUPFAM	SSF56112. Kinase_like. 1 hit. SSF50044. SH3. 1 hit.
PROSITE	PS00107. PROTEIN_KINASE_ATP. 1 hit. PS50011. PROTEIN_KINASE_DOM. 1 hit. PS00109. PROTEIN_KINASE_TYR. 1 hit. PS50001. SH2. 1 hit. PS50002. SH3. 1 hit. [Graphical view]
ProtoNet	Search...
Other
ChEMBL	CHEMBL4362.
NextBio	614514.

Entry information

Entry name

FGR_RAT

Accession

Primary (citable) accession number: Q6P6U0
Secondary accession number(s): Q63206

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 19, 2011
Last sequence update:	July 5, 2004
Last modified:	April 3, 2013
This is version 80 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program