CD115 M-CSFR(macrophage colony stimulating factor), CSF-1R, C-fms
Molecule TypeAntigen ExpressionMolecular Weight
Min / Max
Non-lineage Restricted Molecule
Type 1 glycoprotein
Trophoblast
Muscle, Smooth
Breast
Myeloid Leukemia
Neuronal Cell
Osteoclast
Dendritic Cell
Astrocyte
Cancer cell
150 / 150

Expression
CD115 is expressed primarily on cells of the mononuclear phagocytic lineage such as osteoclasts, dendritic cells, placental trophoblastic cells, breast cells during normal development and lactation, microglia, neurons, and astrocytes.  Under pathological conditions, CD115 is expressed on the myeloid leukemia blast cell, some breast and ovarian cancers, vascular smooth muscle cells in atheroma, and an increased expression in astrocytes and neurons following injury.  CD115 is located on the cytoplasmic membrane.

Structure
MOLECULAR FAMILY NAME:  Belongs to the immunolglobulin tyrosine kinase family.

CD115 is a single-pass type-1 glycoprotein.  It contains a 492 aa extracellular domain which is variable glycosylated and contains 4 Ig-like C2-type domains and 1 Ig-like V-type domain with the N-terminal 3 Ig domains which are required for high affinity of the ligand M-CSF,  a 24 aa transmembrane and a 434 aa cytoplasmic domain which contains a protein tyrosine kinase interrupted by a 70 aa kinase insert domain.  This insertion is necessary for the association of CD115 with phosphatidylinositol 3-kinase (PI 3-kinase).  CD115 is encoded by the c-fms proto-oncogene.  Ligand binding induces and stabilizes dimerization of CD115 and activates the receptor through autophosphorylation in trans.  CD115 belongs to the Ig domain containing receptor kinase kinase family (see CD117, CD135, CD140a and CD140b).  It belongs to a subclass 3 within the family of growth factor receptors with tyrosine kinase activity. Lys593 is predicted to be the site of ATP binding and preceded by the conserved GXGXXG motif.

MOLECULAR MASS
Cell Type Unreduced Reduced
150 kDa

POST-TRANSCRIPTIONAL MODIFICATION: No information.

POST-TRANSLATIONAL MODIFICATION 

Phosphorylation of CD115 at several sites generates binding sites for other signaling molecules.  Phosphorylation of tyrosine 809 is essential for activity.  809 mutant globally impairs kinase function and blocks mitogenic response to CD115 in NIH3T3 cells.  Modification occurs in multiple uncharacterized sites of serine and threonine phosphorylation. 


Ligands
LIGANDS AND MOLECULES ASSOCIATED WITH CD115

CD115 ligand binding activates the receptor kinase through a process of oligomerization and transphosphorylation and all of the biological effects of CSF-1 are mediated by kinase activation.  CSF-1R is phosphorylated at a number of sites, several of which serve as binding sites for other signaling molecules.  Phosphorylation at tyrosine 809 is required for activity and mutation of this site in impairment of function.  CD115 ligand binding induces growth and survival, activation of D type cyclins, activation of ras/raf/MAPK, activation of PI-3 kinase/AKT, activation of STAT1 dependent transcription and receptor endocytosis which requires the Y571 motif, and the Y569A in the mouse inducing a mutant defective in the ligand mediated receptor internalization but Y569F is internalized normally.  Endocytosis is enhanced by c-Cbl mediates ligand-induced receptor multi-ubiquitination.

The binding of macrophage colony-stimulating factor receptor (M-CSF) to CD115 with kDa = 50 pM induces or stabilizes dimerization of the receptor.  This results in kinase activation and Tyr phosphorylation of CD115 itself and other cytoplasmic proteins, including PI 3-kinase.  CD115 is also associated with a G protein, stimulates the translocation of protein kinase C to the membrane, and induces phosphatidylcholine hydrolysis and gene expression.

LIGAND AND MOLECULE ASSOCIATED WITH CD115
Molecule Comment
CSF-1 Binds the extracellular domain of CSF-1R.  This high affinity binding requires the N-terminal 3 Ig domains.  Activates kinase through receptor oligomerization
Phosphotyrosine binding proteins
Src CSF-1R Y561 binds Src
Grb2 CSF-1R Y699P binds Grb2 and Mona
Mona CSF-1R Y699P binds Grb2 and Mona
STAT1 CSF-1R Y708P binds STAT1
PI-3 kinase p85 subunit CSF-1R Y723P binds PI-3 kinase p85 subunit
FMIP CSF-1R binds fms interacting protein (FMIP)


Function
CD115 is the receptor for the growth factor M-CSF and is a protein tyrosine kinase that mediates the functions of M-CSF.  CD115 is a cytokine that plays a role in the growth, survival and differentiation of mononuclear phagocytic cells and dendritic cells.  The receptor mediates most if not all biological effects of this cytokine.  It also regulates trophoblasts.  CD115 and CSF-1 are thought to be involved in autrocrine and paracrine interactions that may regulate trophoblast and/or decidual cell function.  CD115 stimulates the survival, proliferation and differentiation of monocytes and macrophages and their bone marrow progenitors. The inductive vs permissive role in differentiation is not established but CD115 generally has a priming role in macrophage activation.

BIOCHEMICAL ACTIVITY

CD115 has CSF-1 binding and protein tyrosine kinase.

DISEASE RELEVANCE AND FUNCTION OF CD115 IN INTACT ANIMAL

CD115 appears to have benefit in promoting the recovery of myeloid cells and of the monocyte/macrophage lineage following chemotherapy reducing the number and severity of fungal infections.  It does not alter therapeutic response and is not associated with early relapse in acute myelogenous leukemia (AML).  Mutations in this gene have been associated with the predisposition to myeloid malignancy.  There are case reports describing the use of CD115  that has been used in the treatment of aplastic anemia and a phase 1 clinical trial in meloma has been conducted.  The loss of both alleles of CD115 has been demonstrated in patients with myelodysplastic syndrome.




Comments
MOLECULAR INTERACTIONS -
PROTEINS AND DNA ELEMENTS WHICH REGULATE TRANSCRIPTION OF CD115: No information.

SUBSTRATES: No information.

ENZYMES WHICH MODIFY CD115: No information.

ADDITIONAL INSIGHTS

v-fms is a viral oncogene present in the feline McDonough sarcoma virus and carries several substitution mutations including those conferring full transforming activity to feline c-fms 301 and 374 and a carboxyl terminal deletion and causing constitutive activation of its kinase.  v-fms mutations at 301 of the human CSF-1R gene confer a constitutively active phenotype that is enhanced by mutations at 969 and have been observed in myeloid leukemia.  The role of CSF-1R in breast cancer is controversial.  CSF-1R expression has been reported to be associated with an invasive phenotype in breast cancers, but CSF-1R transfected breast cancer cell lines also show growth arrest in response to CSF-1R.



Database accession numbers
AnimalPIRSWISSPROTEMGBL/GENBANK
 
HumanEntrezgene 1436P07333
MouseP09581X06368
Antibodies

Revised June 25, 2008


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