Biology and action of colony--stimulating factor-1.
Colony-stimulating factor-1 (CSF-1), also known as macrophage colony-stimulating factor, controls the survival, proliferation, and differentiation of mononuclear phagocytes and regulates cells of the females reproductive tract. It appears to play an autocrine and/or paracrine role in cancers of the ovary, endometrium, breast, and myeloid and lymphoid tissues. Through alternative mRNA splicing and differential post-translational proteolytic processing, CSF-1 can either be secreted into the circulation as a glycoprotein or chondroitin sulfate-containing proteoglycan or be expressed as a membrane-spanning glycoprotein on the surface of CSF-1-producing cells. Studies with the op/op mouse, which possesses an inactivating mutation in the CSF-1 gene, have established the central role of CSF-1 in directly regulating osteoclastogenesis and macrophage production. CSF-1 appears to preferentially regulate the development of macrophages found in tissues undergoing active morphogenesis and/or tissue remodeling. These CSF-1 dependent macrophages may, via putative trophic and/or scavenger functions, regulate characteristics such as dermal thickness, male fertility, and neural processing. Apart from its expression on mononuclear phagocytes and their precursors, CSF-1 receptor (CSF-1R) expression on certain nonmononuclear phagocytic cells in the female reproductive tract and studies in the op/op mouse indicate that CSF-1 plays important roles in female reproduction. Restoration of circulating CSF-1 to op/op mice has preliminarily defined target cell populations that are regulated either humorally or locally by the synthesis of cell-surface CSF-1 or by sequestration of the CSF-1 proteoglycan. The CSF-1R is a tyrosine kinase encoded by the c-fms proto-oncogene product. Studies by several groups have used cells expressing either the murine or human CSF-1R in fibroblasts to pinpoint the requirement of kinase activity and the importance of various receptor tyrosine phosphorylation sites for signaling pathways stimulated by CSF-1. To investigate post-CSF-1R signaling in the macrophage, proteins that are rapidly phosphorylated on tyrosine in response to CSF-1 have been identified, together with proteins associated with them. Studies on several of these proteins, including protein tyrosine phosphates 1C, the c-cbl proto-oncogene product, and protein tyrosine phosphatase-phi are discussed.
Stanley
E R
ER
Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, New York, New York 10461, USA.
Berg
K L
KL
Einstein
D B
DB
Lee
P S
PS
Pixley
F J
FJ
Wang
Y
Y
Yeung
Y G
YG
D000818:Animals; D017173:Caenorhabditis elegans / Q000196:embryology / Q000235:genetics; D005314:Embryonic and Fetal Development; D005260:Female; D015801:Helminth Proteins / Q000502:physiology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D008264:Macrophages / Q000187:drug effects / Q000502:physiology; D008297:Male; D008565:Membrane Proteins / Q000502:physiology; D051379:Mice; D008817:Mice, Mutant Strains; D010022:Osteopetrosis / Q000196:embryology / Q000235:genetics; D010766:Phosphorylation; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000502:physiology; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000502:physiology; D050721:Proto-Oncogene Proteins c-cbl; D011519:Proto-Oncogenes; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000378:metabolism; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases
D015801:Helminth Proteins; D047908:Intracellular Signaling Peptides and Proteins; C000715470:MAS1 protein, human; D008565:Membrane Proteins; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D016173:Macrophage Colony-Stimulating Factor; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D016186:Receptor, Macrophage Colony-Stimulating Factor; C509249:PTPN6 protein, human; C516888:PTPRO protein, human; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C509248:Ptpn6 protein, mouse; C516890:Ptpro protein, mouse; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3; C067419:CBL protein, human; C493849:Cbl protein, mouse