Q00495 (CSF1R_RAT) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Macrophage colony-stimulating factor 1 receptor

Alternative name(s):
CSF-1 receptor
Short name=CSF-1-R
Short name=CSF-1R
Short name=M-CSF-R
EC=2.7.10.1
Proto-oncogene c-Fms
CD_antigen=CD115

Gene names

Name:	Csf1r
Synonyms:	Csfmr, Fms

Organism

Rattus norvegicus (Rat)

Taxonomic identifier

10116 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Rattus

Protein attributes

Sequence length	978 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	Tyrosine-protein kinase that acts as cell-surface receptor for CSF1 and IL34 and plays an essential role in the regulation of survival, proliferation and differentiation of hematopoietic precursor cells, especially mononuclear phagocytes, such as macrophages and monocytes. Promotes the release of proinflammatory chemokines in response to IL34 and CSF1, and thereby plays an important role in innate immunity and in inflammatory processes. Plays an important role in the regulation of osteoclast proliferation and differentiation, the regulation of bone resorption, and is required for normal bone and tooth development. Required for normal male and female fertility, and for normal development of milk ducts and acinar structures in the mammary gland during pregnancy. Promotes reorganization of the actin cytoskeleton, regulates formation of membrane ruffles, cell adhesion and cell migration, and promotes cancer cell invasion. Activates several signaling pathways in response to ligand binding. Phosphorylates PIK3R1, PLCG2, GRB2, SLA2 and CBL. Activation of PLCG2 leads to the production of the cellular signaling molecules diacylglycerol and inositol-1,4,5-trisphosphate, that then lead to the activation of protein kinase C family members, especially PRKCD. Phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, leads to activation of the AKT1 signaling pathway. Activated CSF1R also mediates activation of the MAP kinases MAPK1/ERK2 and/or MAPK3/ERK1, and of the SRC family kinases SRC, FYN and YES1. Activated CSF1R transmits signals both via proteins that directly interact with phosphorylated tyrosine residues in its intracellular domain, or via adapter proteins, such as GRB2. Promotes activation of STAT family members STAT3, STAT5A and/or STAT5B. Promotes tyrosine phosphorylation of SHC1 and INPP5D/SHIP-1. Receptor signaling is down-regulated by protein phosphatases, such as INPP5D/SHIP-1, that dephosphorylate the receptor and its downstream effectors, and by rapid internalization of the activated receptor By similarity. Ref.2
Catalytic activity	ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.
Enzyme regulation	Present in an inactive conformation in the absence of bound ligand. CSF1 or IL34 binding leads to dimerization and activation by autophosphorylation on tyrosine residues By similarity.
Subunit structure	Monomer. Homodimer. Interacts with CSF1 and IL34. Interaction with dimeric CSF1 or IL34 leads to receptor homodimerization. Interacts with INPPL1/SHIP2 and THOC5. Interacts (tyrosine phosphorylated) with PLCG2 (via SH2 domain). Interacts (tyrosine phosphorylated) with PIK3R1 (via SH2 domain). Interacts (tyrosine phosphorylated) with FYN, YES1 and SRC (via SH2 domain). Interacts (tyrosine phosphorylated) with CBL, GRB2 and SLA2 By similarity.
Subcellular location	Cell membrane; Single-pass type I membrane protein. Note: The autophosphorylated receptor is ubiquitinated and internalized, leading to its degradation By similarity.
Domain	The juxtamembrane domain functions as autoinhibitory region. Phosphorylation of tyrosine residues in this region leads to a conformation change and activation of the kinase By similarity. The activation loop plays an important role in the regulation of kinase activity. Phosphorylation of tyrosine residues in this region leads to a conformation change and activation of the kinase By similarity.
Post-translational modification	Autophosphorylated in response to CSF1 or IL34 binding. Phosphorylation at Tyr-559 is important for normal down-regulation of signaling by ubiquitination, internalization and degradation. Phosphorylation at Tyr-559 and Tyr-807 is important for interaction with SRC family members, including FYN, YES1 and SRC, and for subsequent activation of these protein kinases. Phosphorylation at Tyr-697 and Tyr-921 is important for interaction with GRB2. Phosphorylation at Tyr-721 is important for interaction with PIK3R1. Phosphorylation at Tyr-721 and Tyr-807 is important for interaction with PLCG2. Phosphorylation at Tyr-974 is important for interaction with CBL By similarity. Ubiquitinated. Becomes rapidly polyubiquitinated after autophosphorylation, leading to its degradation By similarity.
Sequence similarities	Belongs to the protein kinase superfamily. Tyr protein kinase family. CSF-1/PDGF receptor subfamily. Contains 5 Ig-like C2-type (immunoglobulin-like) domains. Contains 1 protein kinase domain.

Ontologies

Keywords
Biological process	Immunity Inflammatory response Innate immunity
Cellular component	Cell membrane Membrane
Disease	Proto-oncogene
Domain	Immunoglobulin domain Repeat Signal Transmembrane Transmembrane helix
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Receptor Transferase Tyrosine-protein kinase
PTM	Disulfide bond Glycoprotein Phosphoprotein Ubl conjugation
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological process	cell proliferation Inferred from direct assay. Source: RGD cellular response to macrophage colony-stimulating factor stimulus Inferred from sequence or structural similarity. Source: UniProtKB osteoclast differentiation Inferred from sequence or structural similarity. Source: UniProtKB peptidyl-tyrosine phosphorylation Inferred from sequence or structural similarity. Source: UniProtKB phosphatidylinositol metabolic process Inferred from sequence or structural similarity. Source: UniProtKB phosphatidylinositol-mediated signaling Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of ERK1 and ERK2 cascade Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of cell migration Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of cell proliferation Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of osteoclast differentiation Inferred from mutant phenotype Ref.2. Source: RGD positive regulation of protein serine/threonine kinase activity Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of tyrosine phosphorylation of Stat3 protein Inferred from sequence or structural similarity. Source: UniProtKB protein autophosphorylation Inferred from sequence or structural similarity. Source: UniProtKB regulation of actin cytoskeleton reorganization Inferred from sequence or structural similarity. Source: UniProtKB regulation of bone resorption Inferred from mutant phenotype Ref.2. Source: UniProtKB regulation of cell shape Inferred from sequence or structural similarity. Source: UniProtKB ruffle organization Inferred from sequence or structural similarity. Source: UniProtKB skeletal muscle tissue development Inferred from expression pattern Ref.1. Source: RGD transmembrane receptor protein tyrosine kinase signaling pathway Inferred from sequence or structural similarity. Source: UniProtKB
Cellular component	cell surface Inferred from sequence or structural similarity. Source: UniProtKB integral to membrane Inferred from electronic annotation. Source: UniProtKB-KW
Molecular function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW cytokine binding Inferred from sequence or structural similarity. Source: UniProtKB macrophage colony-stimulating factor receptor activity Inferred from sequence or structural similarity. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Signal peptide	1 – 19	19	By similarity
	Chain	20 – 978	959	Macrophage colony-stimulating factor 1 receptor		PRO_0000016767
Regions
	Topological domain	20 – 515	496	Extracellular Potential
	Transmembrane	516 – 536	21	Helical; Potential
	Topological domain	537 – 978	442	Cytoplasmic Potential
	Domain	24 – 104	81	Ig-like C2-type 1
	Domain	107 – 197	91	Ig-like C2-type 2
	Domain	204 – 298	95	Ig-like C2-type 3
	Domain	299 – 397	99	Ig-like C2-type 4
	Domain	398 – 503	106	Ig-like C2-type 5
	Domain	580 – 914	335	Protein kinase
	Nucleotide binding	586 – 594	9	ATP By similarity
	Region	540 – 572	33	Regulatory juxtamembrane domain By similarity
	Region	794 – 816	23	Activation loop By similarity
Sites
	Active site	776	1	Proton acceptor By similarity
	Binding site	614	1	ATP By similarity
Amino acid modifications
	Modified residue	544	1	Phosphotyrosine; by autocatalysis By similarity
	Modified residue	554	1	Phosphotyrosine By similarity
	Modified residue	559	1	Phosphotyrosine; by autocatalysis By similarity
	Modified residue	560	1	Phosphothreonine By similarity
	Modified residue	565	1	Phosphothreonine By similarity
	Modified residue	697	1	Phosphotyrosine; by autocatalysis By similarity
	Modified residue	706	1	Phosphotyrosine; by autocatalysis By similarity
	Modified residue	711	1	Phosphoserine By similarity
	Modified residue	714	1	Phosphoserine By similarity
	Modified residue	721	1	Phosphotyrosine; by autocatalysis By similarity
	Modified residue	807	1	Phosphotyrosine; by autocatalysis By similarity
	Modified residue	921	1	Phosphotyrosine; by autocatalysis By similarity
	Modified residue	974	1	Phosphotyrosine; by autocatalysis By similarity
	Glycosylation	45	1	N-linked (GlcNAc...) Potential
	Glycosylation	73	1	N-linked (GlcNAc...) Potential
	Glycosylation	302	1	N-linked (GlcNAc...) Potential
	Glycosylation	335	1	N-linked (GlcNAc...) Potential
	Glycosylation	389	1	N-linked (GlcNAc...) Potential
	Glycosylation	410	1	N-linked (GlcNAc...) Potential
	Glycosylation	449	1	N-linked (GlcNAc...) Potential
	Glycosylation	478	1	N-linked (GlcNAc...) Potential
	Glycosylation	491	1	N-linked (GlcNAc...) Potential
	Disulfide bond	42 ↔ 84		By similarity
	Disulfide bond	127 ↔ 177		By similarity
	Disulfide bond	224 ↔ 278		By similarity
	Disulfide bond	417 ↔ 483		By similarity

Sequences

	Sequence		Length	Mass (Da)
	Q00495 [UniParc]. Last modified April 1, 1993. Version 1. Checksum: 0A68456EF56BC7E3	FASTA	978	109,264
	10 20 30 40 50 60 MELGPPLVLL LATVWHGQGA PVIEPSGPEL VVEPGETVTL RCVSNGSVEW DGPISPYWTL 70 80 90 100 110 120 DPESPGSTLT TRNATFKNTG TYRCTELEDP MAGSTTIHLY VKDPAHSWNL LAQEVTVVEG 130 140 150 160 170 180 QEAVLPCLIT DPALKDSVSL MREGGRQVLR KTVYFFSAWR GFIIRKAKVL DSNTYVCKTM 190 200 210 220 230 240 VNGRESTSTG IWLKVNRVHP EPPQIKLEPS KLVRIRGEAA QIVCSATNAE VGFNVILKRG 250 260 270 280 290 300 DTKLEIPLNS DFQDNYYKKV RALSLNAVDF QDAGIYSCVA SNDVGTRTAT MNFQVVESAY 310 320 330 340 350 360 LNLTSEQSLL QEVSVGDSLI LTVHADAYPS IQHYNWTYLG PFFEDQRKLE FITQRAIYRY 370 380 390 400 410 420 TFKLFLNRVK ASEAGQYFLM AQNKAGWNNL TFELTLRYPP EVSVTWMPVN GSDVLFCDVS 430 440 450 460 470 480 GYPQPSVTWM ECRGHTDRCD EAQALQVWND THPEVLSQKP FDKVIIQSQL PIGTLKHNMT 490 500 510 520 530 540 YFCKTHNSVG NSSQYFRAVS LGQSKQLPDE SLFTPVVVAC MSVMSLLVLL LLLLLYKYKQ 550 560 570 580 590 600 KPKYQVRWKI IERYEGNSYT FIDPTQLPYN EKWEFPRNNL QFGKTLGAGA FGKVVEATAF 610 620 630 640 650 660 GLGKEDAVLK VAVKMLKSTA HADEKEALMS ELKIMSHLGQ HENIVNLLGA CTHGGPVLVI 670 680 690 700 710 720 TEYCCYGDLL NFLRRKAEAM LGPSLSPGQD SEGDSSYKNI HLEKKYVRRD SGFSSQGVDT 730 740 750 760 770 780 YVEMRPVSTS SSDSFFKQDL DKEPSRPLEL WDLLHFSSQV AQGMAFLASK NCIHRDVAAR 790 800 810 820 830 840 NVLLTSGHVA KIGDFGLARD IMNDSNYVVK GNARLPVKWM APESILYCVY TVQSDVWSYG 850 860 870 880 890 900 ILLWEIFSLG LNPYPGILVN NKFYKLVKDG YQMAQPVFAP KNIYSIMQSC WDLEPTRRPT 910 920 930 940 950 960 FQQICFLLQE QARLERRDQD YANLPSSGGS SGSDSGGGSS GGSSSEPEEE SSSEHLACCE 970 PGDIAQPLLQ PNNYQFAC

References

[1]	"Molecular cloning of CSF-1 receptor from rat myoblasts. Sequence analysis and regulation during myogenesis." Borycki A.G., Guillier M., Leibovitch M.P., Leibovitch S.A. Growth Factors 6:209-218(1992) [PubMed: 1389227] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Strain: Wistar. Tissue: Skeletal muscle.
[2]	"A c-fms tyrosine kinase inhibitor, Ki20227, suppresses osteoclast differentiation and osteolytic bone destruction in a bone metastasis model." Ohno H., Kubo K., Murooka H., Kobayashi Y., Nishitoba T., Shibuya M., Yoneda T., Isoe T. Mol. Cancer Ther. 5:2634-2643(2006) [PubMed: 17121910] [Abstract] Cited for: FUNCTION IN BONE RESORPTION.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	X61479 mRNA. Translation: CAA43706.1.
IPI	IPI00199372.
PIR	S16385. I60321.
UniGene	Rn.72599.
3D structure databases
ProteinModelPortal	Q00495.
SMR	Q00495. Positions 541-916.
ModBase	Search...
Proteomic databases
PRIDE	Q00495.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Organism-specific databases
RGD	2425. Csf1r.
Phylogenomic databases
HOVERGEN	HBG004335.
Enzyme and pathway databases
BRENDA	2.7.10.1. 5301.
Gene expression databases
Genevestigator	Q00495.
Family and domain databases
InterPro	IPR007110. Ig-like. IPR013783. Ig-like_fold. IPR013098. Ig_I-set. IPR003599. Ig_sub. IPR003598. Ig_sub2. IPR011009. Kinase-like_dom. IPR000719. Prot_kinase_cat_dom. IPR017441. Protein_kinase_ATP_BS. IPR001245. Ser-Thr/Tyr_kinase. IPR008266. Tyr_kinase_AS. IPR020635. Tyr_kinase_cat_dom. IPR016243. Tyr_kinase_CSF1/PDGF_rcpt. IPR001824. Tyr_kinase_rcpt_3_CS. [Graphical view]
Gene3D	G3DSA:2.60.40.10. Ig-like_fold. 5 hits.
Pfam	PF07679. I-set. 1 hit. PF07714. Pkinase_Tyr. 1 hit. [Graphical view]
PIRSF	PIRSF000615. TyrPK_CSF1-R. 1 hit.
SMART	SM00409. IG. 3 hits. SM00408. IGc2. 1 hit. SM00219. TyrKc. 1 hit. [Graphical view]
SUPFAM	SSF56112. Kinase_like. 1 hit.
PROSITE	PS50835. IG_LIKE. 4 hits. PS00107. PROTEIN_KINASE_ATP. 1 hit. PS50011. PROTEIN_KINASE_DOM. 1 hit. PS00109. PROTEIN_KINASE_TYR. 1 hit. PS00240. RECEPTOR_TYR_KIN_III. 1 hit. [Graphical view]
ProtoNet	Search...

Entry information

Entry name

CSF1R_RAT

Accession

Primary (citable) accession number: Q00495

Entry history

Integrated into UniProtKB/Swiss-Prot:	April 1, 1993
Last sequence update:	April 1, 1993
Last modified:	December 14, 2011
This is version 111 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program