BIOLOGY AND ACTION OF COLONY-STIMULATING FACTOR-I

Colony-stimulating factor-1 (CSF-1), also known as macrophage colony-s timulating factor, controls the survival, proliferation, and different iation of mononuclear phagocytes and regulates cells of the female rep roductive tract. It appears to play an autocrine and/or paracrine role in cancers of the ovary, endometrium, breast, and myeloid and lymphoi d tissues. Through alternative mRNA splicing and differential post-tra nslational proteolytic processing, CSF-1 can either be secreted into t he circulation as a glycoprotein or chondroitin sulfate-containing pro teoglycan or be expressed as a membrane-spanning glycoprotein on the s urface of CSF-l-producing cells. Studies with the op/op mouse, which p ossesses an inactivating mutation in the CSF-1 gene, have established the central role of CSF-1 in directly regulating osteoclastogenesis an d macrophage production. CSF-1 appears to preferentially regulate the development of macrophages found in tissues undergoing active morphoge nesis and/or tissue remodeling. These CSF-1 dependent macrophages may, via putative trophic and/or scavenger functions, regulate characteris tics such as dermal thickness, male fertility, and neural processing. Apart from its expression on mononuclear phagocytes and their precurso rs, CSF-1 receptor(CSF-1R) expression on certain nonmononuclear phagoc ytic cells in the female reproductive tract and studies in the op/op m ouse indicate that CSF-1 plays important roles in female reproduction. Restoration of circulating CSF-1 to op/op mice has preliminarily defi ned target cell populations that are regulated either humorally or loc ally 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 pinpoin t the requirement of kinase activity and the importance of various rec eptor tyrosine phosphorylation sites for signaling pathways stimulated by CSF-1. To investigate post CSF-1R signaling in the macrophage, pro teins that are rapidly phosphorylated on tyrosine in response to CSF-1 have been identified, together with proteins associated with them. St udies on several of these proteins, including protein tyrosine phospha tase 1C, the c-cbl proto-oncogene product, and protein tyrosine phosph atase-phi are discussed. (C) 1997 Wiley-Liss, Inc.