Colony-Stimulating Factor Receptor (CSF-1R); c-fms. By Nate Reynolds

Questions to Be Answered What is the CSF-1 Receptor? What does the CSF-1 Receptor do in the normal cell and how does it do it? What is the link between the CSF-1 Receptor and cancer?

What is the CSF-1 Receptor? It is a receptor tyrosine kinase. It has 4 domains: Extracellular domain that binds the ligand Membrane spanning domain Cytoplasmic domain that has tyrosine kinase activity C-terminus Its ligand is macrophage colony stimulating factor (M-CSF or CSF-1).

What does CSF-1 Receptor do in the normal cell? It is responsible for regulating the growth, proliferation, and differentiation of monocyte and macrophage precursors. The binding of M-CSF to its receptor during G-1 results in a commitment through the progression of DNA synthesis and cell division. It has also been shown to be expressed in normal trophoblast and fibroblast cells.

How does the CSF-1 Receptor work normally? It binds its ligand, dimerizes, and phosphorylates itself. Its phosphorylated tyrosine residues serve as binding sites for other proteins via SH2 domains. A signal cascade is produced culminating in mitogenesis and morphological changes. 1) Believed to activate the Ras pathway as well as the GTP binding proteins Rac and Rho.

How does CSF-1 Receptor work normally? Once activated the receptor is internalized and degraded. This is an important part of the regulation process; it disallows the continued propagation of the signal.

What is the link between CSF-1 Receptor and cancer? The gene that encodes for the CSF-1 Receptor (c-fms) was found as a homolog to v-fms, or feline sarcoma virus. V-fms encodes a constitutively active form of the receptor, resulting in increased growth and proliferation, as well as changes in morphology.

Understanding cancer: Differences between c-fms and v-fms Differences between c-fms protein and v-fms protein occur in three places: The extracellular domain The intracellular domain The C-terminus

Differences between c-fms and v-fms: The extracellular domain In v-fms a leucine at amino acid 301 is changed to serine. This point mutation alone causes some transformation, but not as much as pure v-fms. Likely that point mutation causes a conformational changes similar to the one caused by the binding of the ligand.

The intracellular domain In v-fms tyrosine residue Y807 represents a major autophosphorylation site. Replacing this residue with phenylalanine in the v-fms gene resulted in no change in cell growth or proliferation. It did impact morphology, reverting the cells back to their untransformed state.

The intracellular domain When phosphorylated Y807 interacts with p120RasGap and p190RhoGap. Interaction with and phosphorylation of p120RasGap is an important step in the cascade of events leading to the breakdown of the actin cytoskeleton.

The C-terminus The C-terminus of c-fms contains 40-50 amino acids depending on the species; the v-fms protein contains 11 different residues. A chimera of c-fms and the v-fms C-terminus does not transform cells in the absence of the ligand, M-CSF 1.

The C-terminus The C-terminus is a negative regulator, likely involved in the internalization, ubiquitination, and degradation of the CSF-1 Receptor. Autophosphorylation of Tyr 973 in the C-terminus region allows binding of c-Cbl, which leads to ubiquitination and degradation.

Putting it together . . . Point mutations in the extracellular domain can change the protein’s conformation to a constitutively active form. Once activated autophosphorylation of tyrosine residues in the intracellular domain can affect changes in morphology. The C-terminus acts as a negative regulator. A combination of mutations leads to the most transformed cells.

CSF-1 Receptor and Cancer: More than a question of mutations In humans CSF-1 Receptor is over-expressed in certain types of cancer: Ovarian epithelial carcinomas Endometrial carcinomas Mammary carcinomas Various leukemias

Regulation of c-fms The c-fms gene is under the control of two separate promoters, yielding two mRNA isoforms but identical proteins. Promoter 1 is active in placental cells and promoter 2 is active in macrophages. These promoters are abnormal (lacking TATTA-box elements and GC rich regions). The regulation of c-fms is still enigmatic.

To conclude . . . Despite a lack of knowledge about the regulation of the c-fms gene, the presence of v-fms provides hope for cell-specific therapies. V-fms gives clues as to what regions of the c-fms protein are important for both morphological transformation and mitogenesis.