macrophage colony stimulating factor 1 receptor selections

macrophage colony-stimulating factor 1 receptor; CSF-1 receptor; CSF-1-R; CSF-1R; M-CSF-R; proto-oncogene c-Fms; CD115 (CSF1R, FMS)

Function: - protein tyrosine-kinase receptor for CSF1 & IL34 - interacts with INPPL1/SHIP2 & THOC5 (putative) - role in regulation of survival, proliferation & differentiation of hematopoietic precursor cells, especially mononuclear phagocytes, such as macrophages & monocytes - promotes the release of proinflammatory chemokines in response to IL34 & CSF1, & thus plays a role in innate immunity & in inflammatory processes - role in regulation of osteoclast proliferation & differentiation, regulation of bone resorption - required for normal bone & tooth development - required for normal male & female fertility, & for normal development of milk ducts & acinar structures in the mammary gland during pregnancy - promotes reorganization of the actin cytoskeleton, regulates formation of membrane ruffles, cell adhesion & cell migration - phosphorylates PIK3R1, PLCG2, GRB2, SLA2 & CBL activation of PLCG2 leads to the production of the cellular signaling molecules diacylglycerol & 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 &/or MAPK3/ERK1, & of the SRC family kinases SRC, FYN & YES1 - activated CSF1R transmits signals both via proteins that directly interact with phosphorylated Tyr in its intracellular domain, or via adapter proteins, such as GRB2 - promotes activation of STAT family members STAT3, STAT5A &/or STAT5B - promotes Tyr phosphorylation of SHC1 & INPP5D/SHIP-1 - receptor signaling is down-regulated by protein phosphatases, such as INPP5D/SHIP-1, that dephosphorylate the receptor & its downstream effectors, & by rapid internalization of the activated receptor - present in an inactive conformation in the absence of bound ligand - CSF1 or IL34 binding leads to dimerization & activation by autophosphorylation on Tyr - autophosphorylated in response to CSF1 or IL34 binding - phosphorylation at Tyr-561 plays a role in normal down-regulation of signaling by ubiquitination, internalization & degradation - phosphorylation at Tyr-561 & Tyr-809 plays a role in interaction with SRC family members, including FYN, YES1 & SRC, & for subsequent activation of these protein kinases - phosphorylation at Tyr-699 & Tyr-923 plays a role in interaction with GRB2 - phosphorylation at Tyr-723 plays a role in interaction with PIK3R1 - phosphorylation at Tyr-708 plays a role in normal receptor degradation - phosphorylation at Tyr-723 & Tyr-809 plays a role in interaction with PLCG2 - phosphorylation at Tyr-969 plays a role in interaction with CBL - ubiquitinated - rapidly polyubiquitinated after autophosphorylation, leading to its degradation - interacts with INPPL1/SHIP2 & THOC5 (putative) - interacts with CSF1 & IL34 - interaction with dimeric CSF1 or IL34 leads to receptor homodimerization - interacts (Tyr phosphorylated) with PLCG2 (via SH2 domain) - interacts (Tyr phosphorylated) with PIK3R1 (via SH2 domain) - interacts (Tyr phosphorylated) with FYN, YES1 & SRC (via SH2 domain) - interacts (Tyr phosphorylated) with CBL, GRB2 & SLA2 Inhibition: - 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 & GW2580 Structure: - monomer, homodimer - the juxtamembrane domain functions as autoinhibitory region - phosphorylation of Tyr in this region leads to a conformation change & activation of kinase actiivity - belongs to the protein kinase superfamily, Tyr protein kinase family, CSF-1/PDGF receptor subfamily - contains 5 Ig-like C2-type domains (immunoglobulin-like) - contains 1 protein kinase domain Compartment: - plasma membrane; single-pass type 1 membrane protein Expression: - expressed in bone marrow & in differentiated blood mononuclear cells - up-regulated by glucocorticoids - tissue distribution: a) macrophages & precursors b) osteoclasts c) placental trophoblast d) breast tissue e) microglia f) neurons g) astrocytes - distribution in tumors a) AML ~10% b) endometrial cancers (some) c) ovarian cancers (some) d) breast cancers (some) e) vascular smooth muscle cells in atheromas f) choriocarcinoma cells Pharmacology: - inhibited by chemotherapeutic agents: - imatinib (Gleevec) - dasatinib (Sprycel) - sunitinib (Sutent) - masitinib (Masican) Pathology: - deficiency associated with a) abnormal bone remodeling b) osteopetrosis c) abnormal breast development d) decreased fertility - aberrant expression of CSF1 or CSF1R a) can promote cancer cell proliferation, invasion & formation of metastases - overexpression of CSF1 or CSF1R is observed in some breast cancer, ovarian cancer, prostate cancer, & endometrial cancer b) may play a role in inflammatory diseases, such as rheumatoid arthritis, glomerulonephritis, atherosclerosis, & allograft rejection - defects in CSF1R are the cause of leukoencephalopathy, diffuse hereditary, with spheroids

Interactions

molecular events

General

cluster-of-differentiation antigen; cluster designation antigen; CD antigen fms receptor human longevity protein proto oncogene protein

Properties

SIZE: entity length = 972 aa MW = 108 kD COMPARTMENT: cellular membrane STATE: active state MOTIF: signal sequence {1-19} immunoglobulin superfamily domain {21-104} MOTIF: cysteine residue {C42} MODIFICATION: cysteine residue {C84} N-glycosylation site {N45} N-glycosylation site {N73} cysteine residue {C84} MODIFICATION: cysteine residue {C42} immunoglobulin superfamily domain {107-197} MOTIF: cysteine residue {C127} MODIFICATION: cysteine residue {C177} N-glycosylation site {N153} cysteine residue {C177} MODIFICATION: cysteine residue {C127} immunoglobulin superfamily domain {203-290} MOTIF: cysteine residue {C224} MODIFICATION: cysteine residue {C278} N-glycosylation site {N240} N-glycosylation site {N275} cysteine residue {C278} MODIFICATION: cysteine residue {C224} immunoglobulin superfamily domain {299-399} MOTIF: N-glycosylation site {N302} N-glycosylation site {N335} N-glycosylation site {N353} immunoglobulin superfamily domain {402-502} MOTIF: N-glycosylation site {N412} cysteine residue {C419} MODIFICATION: cysteine residue {C485} N-glycosylation site {N428} N-glycosylation site {N480} cysteine residue {C485} MODIFICATION: cysteine residue {C419} transmembrane domain {518-538} Regulatory juxtamembrane {542-574} MOTIF: Tyr phosphorylation site {Y546} Ser phosphorylation site {S555} Tyr phosphorylation site {Y556} Tyr phosphorylation site {Y561} Thr phosphorylation site {T562} Thr phosphorylation site {T567} kinase domain SITE: 582-910 MOTIF: ATP-binding site NAME: ATP-binding site SITE: 588-596 ATP-binding site NAME: ATP-binding site SITE: 616-616 Tyr phosphorylation site {Y699} Tyr phosphorylation site {Y708} Ser phosphorylation site {S713} Ser phosphorylation site {S716} Tyr phosphorylation site {Y723} aspartate residue {D778} Activation loop {796-818} Tyr phosphorylation site {Y809} Tyr phosphorylation site {Y923} Tyr phosphorylation site {Y969}

Database Correlations

OMIM correlations UniProt P07333 PFAM correlations Entrez Gene 1436 Kegg hsa:1436 ENZYME 2.7.10.1

References

UniProt :accession P07333
http://www.pathologyoutlines.com/cd100247.html 21 June 2005
Atlas of Genetics & Cytogenetics in Oncology & Haematology http://atlasgeneticsoncology.org/genes/CSF1RID40161ch5q32.html

Component-of

molecular complex

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