Signaling by CSF1 (M-CSF) in myeloid cells

Stable Identifier
R-HSA-9680350
DOI
Type
Pathway
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Homo sapiens
ReviewStatus
5/5
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Colony stimulating factor-1 (CSF1, CSF-1, also called macrophage colony stimulating factor, M-CSF) is a disulfide-linked dimer that stimulates the proliferation and differentiation of mononuclear phagocytes and the survival, proliferation, motility, and anti-inflammatory activity of macrophages (reviewed in Mouchemore et al. 2012, Stanley and Chitu 2014, Ushach and Zlotnik 2016, Dwyer et al. 2017 and inferred from mouse homologs in Caescu et al. 2015). The unliganded CSF1 receptor, CSF1R (CSF-1R) is either clustered or undergoing rapid dimer-monomer transitions at the cell surface (Li and Stanley 1991). The CSF1 dimer initially binds the D2 and D3 extracellular domains of a monomer of CSF1R (Wang et al. 1993, Chihara et al. 2010, Ma et al. 2012, Felix et al. 2015, and inferred from mouse homologs). A second monomer of CSF1R then binds the CSF1:CSF1R complex and the resulting dimerization of CSF1R activates its kinase activity (Elegheert et al. 2011, Felix et al. 2015, and inferred from mouse homologs). CSF1R initially trans-autophosphorylates tyrosine-561 in the juxtamembrane domain, relieving negative autoinhibition of kinase activity, resulting in the trans-autophosphorylation of 7 more tyrosine residues in its cytoplasmic domain (Rohrschneider et al. 1997, Chihara et al. 2010, and inferred from mouse homologs in Xiong et al. 2011).
The PIK3R1 (p85alpha) regulatory subunit of phosphatidylinositol 3-kinase (PI3K) binds phosphotyrosine-723 of CSF1R, phosphorylated SRC binds phosphotyrosine-561 of CSF1R, phosphorylated CBL binds CSF1R associated with SHC, and GRB2:SOS binds CSF1R (Saleem et al. 1995, and inferred from mouse homologs). The resulting activation of the catalytic subunit of PI3K (PIK2CA,B,G) produces phosphatidylinositol 3,4,5-trisphosphate which recruits effectors containing pleckstrin homology domains (PH domains) such as PKB (also called Akt) to the plasma membrane. Pathways activated by PI3K appear to both enhance proliferation, survival, and migration of macrophages (reviewed in Dwyer et al. 2017) and, via induction of miR21, suppress the inflammatory response by targeting mRNAs encoding multiple proinflammatory molecules.
Phospholipase C gamma2 (PLCG2) binds phosphotyrosine-723 of CSF1R, hydrolyzes phosphatidylcholine to yield choline phosphate (phosphocholine) and diacylglycerol, and promotes survival and differentiation of macrophages via PKCdelta (PRKCD) (inferred from mouse homologs).
GRB2 bound to SOS1 (GRB2:SOS1) transiently interacts with phosphotyrosine-699 of CSF1R. SOS1 promotes the exchange of GDP for GTP by KRAS, activating the RAS-RAF-ERK1,2 pathway that causes proliferation of macrophage precursors (inferred from mouse homologs). CBL transiently associates with and ubiquitinates the CSF1R, then is deubiquitinated and returned to the cytoplasm (inferred from mouse homologs).
Phosphorylated CSF1R also recruits STAT1 and STAT3, which are then phosphorylated (inferred from mouse homologs). The role of phosphorylated STAT1,3 in signaling by CSF1R is incompletely characterized.
CSF1R is a target for therapeutics, such as imatinib (reviewed in Kumari et al. 2018).
Literature References
PubMed ID Title Journal Year
27354413 Biological role of granulocyte macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF) on cells of the myeloid lineage

Ushach, I, Zlotnik, A

J. Leukoc. Biol. 2016
20489731 IL-34 and M-CSF share the receptor Fms but are not identical in biological activity and signal activation

Hassan, R, Kimura, F, Suzu, S, Chutiwitoonchai, N, Motoyoshi, K, Hiyoshi, M, Okada, S, Chihara, T

Cell Death Differ. 2010
22153499 Extracellular complexes of the hematopoietic human and mouse CSF-1 receptor are driven by common assembly principles

Vergauwen, B, Verstraete, K, Van Craenenbroeck, K, Svergun, DI, Wu, X, Bracke, N, Elegheert, J, Savvides, SN, Shkumatov, AV, Gutsche, I, Desfosses, A, Brooks, BR

Structure 2011
22483114 Structural basis for the dual recognition of helical cytokines IL-34 and CSF-1 by CSF-1R

Mukhyala, K, Chen, Y, Ma, X, Martin, F, Wu, Y, Lin, WY, Starovasnik, MA, Stawicki, S, Bazan, JF

Structure 2012
22468857 CSF-1 signaling in macrophages: pleiotrophy through phosphotyrosine-based signaling pathways

Mouchemore, KA, Pixley, FJ

Crit Rev Clin Lab Sci 2012
8355686 Identification of the ligand-binding regions in the macrophage colony-stimulating factor receptor extracellular domain

Myles, GM, Brandt, CS, Wang, ZE, Rohrschneider, L, Lioubin, MN

Mol Cell Biol 1993
25573988 Colony stimulating factor-1 receptor signaling networks inhibit mouse macrophage inflammatory responses by induction of microRNA-21

Stanley, ER, Guo, X, Zheng, D, Verma, A, Caescu, CI, Bhagat, TD, Tesfa, L

Blood 2015
24890514 CSF-1 receptor signaling in myeloid cells

Stanley, ER, Chitu, V

Cold Spring Harb Perspect Biol 2014
21041311 A CSF-1 receptor phosphotyrosine 559 signaling pathway regulates receptor ubiquitination and tyrosine phosphorylation

Stanley, ER, Xiong, Y, Yu, W, Song, D, Yeung, YG, Cai, Y

J. Biol. Chem. 2011
1825054 Role of dimerization and modification of the CSF-1 receptor in its activation and internalization during the CSF-1 response

Stanley, ER, Li, W

EMBO J. 1991
26235028 Structure and Assembly Mechanism of the Signaling Complex Mediated by Human CSF-1

Verstraete, K, Felix, J, Callewaert, N, Elegheert, J, Meuris, L, Savvides, SN, De Munck, S

Structure 2015
28629162 Promotion of Tumor Invasion by Tumor-Associated Macrophages: The Role of CSF-1-Activated Phosphatidylinositol 3 Kinase and Src Family Kinase Motility Signaling

Greenland, EL, Dwyer, AR, Pixley, FJ

Cancers (Basel) 2017
7737969 Monocyte colony-stimulating factor stimulates binding of phosphatidylinositol 3-kinase to Grb2.Sos complexes in human monocytes

Saleem, A, Kharbanda, S, Kufe, D, Yuan, ZM

J. Biol. Chem. 1995
8981370 Growth and differentiation signals regulated by the M-CSF receptor

Bourette, RP, Rohrschneider, LR, Myles, GM, Lioubin, MN, Algate, PA, Carlberg, K

Mol Reprod Dev 1997
29679908 Recent advances in colony stimulating factor-1 receptor/c-FMS as an emerging target for various therapeutic implications

Singh, RK, Silakari, O, Kumari, A

Biomed. Pharmacother. 2018
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