UniProt functional annotation for P09581



	UniProt functional annotation for P09581

UniProt code: P09581.

Organism: Mus musculus (Mouse).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; Murinae; Mus; Mus.

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, including the ERK1/2 and the JNK pathway (By similarity). 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. In the central nervous system, may play a role in the development of microglia macrophages (By similarity). {ECO:0000250|UniProtKB:P07333, ECO:0000269|PubMed:10958675, ECO:0000269|PubMed:11756160, ECO:0000269|PubMed:1652061, ECO:0000269|PubMed:16950670, ECO:0000269|PubMed:17353186, ECO:0000269|PubMed:17420255, ECO:0000269|PubMed:17420256, ECO:0000269|PubMed:17972959, ECO:0000269|PubMed:18814279, ECO:0000269|PubMed:20181277, ECO:0000269|PubMed:20504948, ECO:0000269|PubMed:21610095, ECO:0000269|PubMed:21727904, ECO:0000269|PubMed:8007983, ECO:0000269|PubMed:8262059, ECO:0000269|PubMed:9312046}.

Catalytic activity: Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl- [protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA- COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858, ChEBI:CHEBI:82620, ChEBI:CHEBI:456216; EC=2.7.10.1; Evidence={ECO:0000255|PROSITE-ProRule:PRU10028, ECO:0000269|PubMed:8007983, ECO:0000269|PubMed:8262059, ECO:0000269|PubMed:9312046};

Activity 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. Inhibited by imatinib/STI-571 (Gleevec), dasatinib, sunitinib/SU11248, lestaurtinib/CEP-701, midostaurin/PKC-412, Ki20227, linifanib/ABT-869, Axitinib/AG013736, sorafenib/BAY 43-9006 and GW2580. {ECO:0000269|PubMed:15297464, ECO:0000269|PubMed:18814279}.

Subunit: 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. {ECO:0000269|PubMed:10597251, ECO:0000269|PubMed:11850825, ECO:0000269|PubMed:15557176, ECO:0000269|PubMed:1652061, ECO:0000269|PubMed:17353186, ECO:0000269|PubMed:19017797, ECO:0000269|PubMed:21610095, ECO:0000269|PubMed:8007983, ECO:0000269|PubMed:8262059, ECO:0000269|PubMed:9312046}.

Subcellular location: Cell membrane {ECO:0000269|PubMed:17353186, ECO:0000269|PubMed:8007983}; Single-pass type I membrane protein {ECO:0000269|PubMed:17353186, ECO:0000269|PubMed:8007983}. Note=The autophosphorylated receptor is ubiquitinated and internalized, leading to its degradation.

Tissue specificity: Widely expressed. {ECO:0000269|PubMed:20504948}.

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). {ECO:0000250}.

Domain: 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). {ECO:0000250}.

Ptm: 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. Dephosphorylation by PTPN2 negatively regulates downstream signaling and macrophage differentiation. {ECO:0000269|PubMed:11850825, ECO:0000269|PubMed:15297464, ECO:0000269|PubMed:1652061, ECO:0000269|PubMed:17420255, ECO:0000269|PubMed:20504948, ECO:0000269|PubMed:2160591, ECO:0000269|PubMed:21610095, ECO:0000269|PubMed:8007983, ECO:0000269|PubMed:8262059}.

Ptm: Ubiquitinated. Becomes rapidly polyubiquitinated after autophosphorylation, leading to its degradation.

Disruption phenotype: Mice are born at slightly less than the expected Mendelian rate, and the number of surviving mice is significantly reduced after three weeks. Mice are considerably smaller than wild-type littermates and suffer from general skeletal deformities with shortened limbs, increased bone density, and decreased volume of femoral bone marrow. Mice have decreased numbers of circulating monocytes and lymphocytes, decreased numbers of tissue macrophages, paired with an increase in the number of circulating granulocytes. In addition, mice are deaf and have reduced male and female fertility. In females, the duration of the diestrous period is increased, and in pregnant females the lactating mammary gland fails to develop normally. Males mate less frequently and give rise to fewer pregnant females. {ECO:0000269|PubMed:11756160}.

Similarity: Belongs to the protein kinase superfamily. Tyr protein kinase family. CSF-1/PDGF receptor subfamily. {ECO:0000255|PROSITE- ProRule:PRU00159}.

Annotations taken from UniProtKB at the EBI.


Organism:		Mus musculus (Mouse).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; Murinae; Mus; Mus.



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, including the ERK1/2 and the JNK pathway (By similarity). 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. In the central nervous system, may play a role in the development of microglia macrophages (By similarity). {ECO:0000250\|UniProtKB:P07333, ECO:0000269\|PubMed:10958675, ECO:0000269\|PubMed:11756160, ECO:0000269\|PubMed:1652061, ECO:0000269\|PubMed:16950670, ECO:0000269\|PubMed:17353186, ECO:0000269\|PubMed:17420255, ECO:0000269\|PubMed:17420256, ECO:0000269\|PubMed:17972959, ECO:0000269\|PubMed:18814279, ECO:0000269\|PubMed:20181277, ECO:0000269\|PubMed:20504948, ECO:0000269\|PubMed:21610095, ECO:0000269\|PubMed:21727904, ECO:0000269\|PubMed:8007983, ECO:0000269\|PubMed:8262059, ECO:0000269\|PubMed:9312046}.


Catalytic activity:		Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl- [protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA- COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858, ChEBI:CHEBI:82620, ChEBI:CHEBI:456216; EC=2.7.10.1; Evidence={ECO:0000255\|PROSITE-ProRule:PRU10028, ECO:0000269\|PubMed:8007983, ECO:0000269\|PubMed:8262059, ECO:0000269\|PubMed:9312046};
Activity 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. Inhibited by imatinib/STI-571 (Gleevec), dasatinib, sunitinib/SU11248, lestaurtinib/CEP-701, midostaurin/PKC-412, Ki20227, linifanib/ABT-869, Axitinib/AG013736, sorafenib/BAY 43-9006 and GW2580. {ECO:0000269\|PubMed:15297464, ECO:0000269\|PubMed:18814279}.
Subunit:		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. {ECO:0000269\|PubMed:10597251, ECO:0000269\|PubMed:11850825, ECO:0000269\|PubMed:15557176, ECO:0000269\|PubMed:1652061, ECO:0000269\|PubMed:17353186, ECO:0000269\|PubMed:19017797, ECO:0000269\|PubMed:21610095, ECO:0000269\|PubMed:8007983, ECO:0000269\|PubMed:8262059, ECO:0000269\|PubMed:9312046}.
Subcellular location:		Cell membrane {ECO:0000269\|PubMed:17353186, ECO:0000269\|PubMed:8007983}; Single-pass type I membrane protein {ECO:0000269\|PubMed:17353186, ECO:0000269\|PubMed:8007983}. Note=The autophosphorylated receptor is ubiquitinated and internalized, leading to its degradation.
Tissue specificity:		Widely expressed. {ECO:0000269\|PubMed:20504948}.
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). {ECO:0000250}.
Domain:		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). {ECO:0000250}.
Ptm:		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. Dephosphorylation by PTPN2 negatively regulates downstream signaling and macrophage differentiation. {ECO:0000269\|PubMed:11850825, ECO:0000269\|PubMed:15297464, ECO:0000269\|PubMed:1652061, ECO:0000269\|PubMed:17420255, ECO:0000269\|PubMed:20504948, ECO:0000269\|PubMed:2160591, ECO:0000269\|PubMed:21610095, ECO:0000269\|PubMed:8007983, ECO:0000269\|PubMed:8262059}.
Ptm:		Ubiquitinated. Becomes rapidly polyubiquitinated after autophosphorylation, leading to its degradation.
Disruption phenotype:		Mice are born at slightly less than the expected Mendelian rate, and the number of surviving mice is significantly reduced after three weeks. Mice are considerably smaller than wild-type littermates and suffer from general skeletal deformities with shortened limbs, increased bone density, and decreased volume of femoral bone marrow. Mice have decreased numbers of circulating monocytes and lymphocytes, decreased numbers of tissue macrophages, paired with an increase in the number of circulating granulocytes. In addition, mice are deaf and have reduced male and female fertility. In females, the duration of the diestrous period is increased, and in pregnant females the lactating mammary gland fails to develop normally. Males mate less frequently and give rise to fewer pregnant females. {ECO:0000269\|PubMed:11756160}.
Similarity:		Belongs to the protein kinase superfamily. Tyr protein kinase family. CSF-1/PDGF receptor subfamily. {ECO:0000255\|PROSITE- ProRule:PRU00159}.