Early Events in M-CSF Receptor Signaling

Abstract

The M-CSF receptor (M-CSFR) is expressed in monocytes-macrophages and their progenitors, and drives growth and development of this blood cell lineage. The M-CSFR is a member of a small family of growth factor receptors exhibiting related structures but distinct tissue-specific functions. This review discusses the early molecular events in the M-CSF signaling mechanisms, positive signals, negative signals, the possible organization of individual signaling pathways, and the problem of achieving specificity in the signal transduction mechanism.

IL-34 and M-CSF share the receptor Fms but are not identical in biological activity and signal activation

“…When activated, Fms phosphorylates its own tyrosine residues such as Tyr708, Tyr723 and Tyr809, which triggers the interaction of the activated Fms with downstream signaling molecules. 1,3,4 As summarized (Figure 5d), IL-34 phosphorylated these and other residues (Tyr546 and Tyr699) more strongly than M-CSF at 1 min of stimulation (upper panel). The difference in Tyr546 was more obvious than that in other tyrosines.…”

“…1,2 A unique receptor, Fms, the proto-oncogene c-fms products and receptor tyrosine kinase, mediates the biological effects of M-CSF. 3,4 The binding of M-CSF induces the dimerization and activation of the tyrosine kinase activity of Fms. 3,4 This leads to the autophosphorylation of specific tyrosine residues in the Fms cytoplasmic domain and the subsequent interaction of the phosphorylated tyrosine residues with other signaling proteins, which initiates signaling along specific pathways.…”

“…3,4 The binding of M-CSF induces the dimerization and activation of the tyrosine kinase activity of Fms. 3,4 This leads to the autophosphorylation of specific tyrosine residues in the Fms cytoplasmic domain and the subsequent interaction of the phosphorylated tyrosine residues with other signaling proteins, which initiates signaling along specific pathways. [3][4][5] The essential role of the M-CSF/ Fms axis in the mononuclear phagocyte lineage has been well established using naturally occurring M-CSF-deficient op/op mice 6,7 and Fms knockout mice.…”

“…3,4 This leads to the autophosphorylation of specific tyrosine residues in the Fms cytoplasmic domain and the subsequent interaction of the phosphorylated tyrosine residues with other signaling proteins, which initiates signaling along specific pathways. [3][4][5] The essential role of the M-CSF/ Fms axis in the mononuclear phagocyte lineage has been well established using naturally occurring M-CSF-deficient op/op mice 6,7 and Fms knockout mice. 8 Both mice have low body weight, low growth rate and skeletal abnormalities, and are toothless and deficient in most tissue macrophages.…”

E2a/Pbx1 oncogene inhibits terminal differentiation but not myeloid potential of pro-T cells

“…We were willing to determine whether M-CSF receptor (M-CSF-R) is functional in a pro-T progenitor and whether a normal signaling protein such as M-CSF-R could influence the fate of the E2a/Pbx1-immortalized pro-T cell. M-CSF is a key regulator of cells belonging to the monocyte-macrophage lineage (Stanley et al, 1994;Bourette and Rohrschneider, 2000). M-CSF-R, encoded by the c-fms protooncogene, is a member of the class III receptor tyrosine kinase (RTK) family, which includes other RTK involved in the regulation of hematopoiesis or in hematopoietic cell function: the b-receptor for plateletderived growth factor (PDGF), the receptor for SCF and Flt3/flk2 (Scheijen and Griffin, 2002).…”