Professor Emeritus, Department of Developmental & Molecular Biology
Renée E. and Robert A. Belfer Chair in Developmental Biology
Growth Factors and Signaling in Development and Disease: (last updated 1/21/15)
CSF-1 Biology: Colony stimulating factor-1 (CSF-1) is a growth factor which regulates the production of macrophages, osteoclasts, Paneth cells, microglia, neuronal cells and the function of certain non-myeloid cell types in the female reproductive tract. It is expressed as a secreted glycoprotein, secreted proteoglycan or a membrane-spanning, cell-surface glycoprotein. Its effects are mediated via the CSF-1 receptor tyrosine kinase (CSF-1R), the c-fms protooncoprotein. CSF-1-deficient mice are osteopetrotic due to a lack of osteoclasts, have poor fertility, abnormal intestinal development and several other defects related to CSF-1 regulation of macrophages that have critical scavenger and trophic roles in the development, maintenance or function of tissues in which they reside. CSF-1R-deficient mice have a more severe phenotype than CSF-1-deficient mice, due to the existence of a second CSF-1R ligand, interleukin-34 (IL-34), which we have recently shown also acts through another receptor, protein tyrosine phosphatase-zeta, that is expressed on neuronal cells, but on neither microglia, nor macrophages. IL-34 is highly expressed in brain where, with CSF-1, it regulates the development and maintenance of microglia and the differentiation of neural progenitor cells. CSF-1R regulation of macrophages is important in innate immunity, inflammatory diseases, atherosclerosis, obesity and within tumors, for tumor progression and metastasis. Autocrine regulation by CSF-1 has been demonstrated in leukemia and solid tumors. It has recently been shown that dominant inactivating mutations within the kinase domain of the CSF-1R lead to a dementia, adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), and we have identified a mouse model of this disease. Mouse genetic and other approaches are being taken to investigate the developmental and physiological roles of CSF-1 and IL-34, as well as their roles in disease development.
CSF-1 signal transduction: Since phosphorylation of specific CSF-1R intracellular domain tyrosine residues initiate particular signaling pathways, detailed structure-function studies of the CSF-1R are being carried out in macrophages and macrophage progenitor cells. In the analysis of very early post-receptor events, proteins that are rapidly phosphorylated in tyrosine in response to CSF-1 or associated with tyrosine-phosphorylated proteins, approximately 800 in all, have been identified by mass spectrometry. A combination of genetic, proteomic, biochemical and analytical imaging approaches are being used to elucidate the roles and interactions of these signaling proteins in the immediate post-receptor events in CSF-1 signal transduction. Previous studies have identified and elucidated the actions of the protein tyrosine phosphatase SHP-1, that negatively affects cell survival in the absence of CSF-1, the cbl proto-oncogene product, that negatively regulates CSF-1 proliferation signaling by enhancing CSF-1R endocytosis and the protein tyrosine phosphatase, PTP-phi, that mediates CSF-1-induced morphological changes, adhesion and motility, via its action on a specific substrate, paxillin. One of the tyrosine phosphorylated proteins we have identified and studied is the macrophage F-actin associated and tyrosine phosphorylated protein (MAYP), also known as proline, serine, threonine phosphatase-interacting protein 2 (PSTPIP2). PSTPIP2 is an F-BAR protein that coordinates processes involving the cell membrane and actin cytoskeleton. We have shown that it is a negative feedback regulator of CSF-1R-mediated osteoclast and macrophage production and that a loss-of-function mutation in PSTPIP2 lead to an autoinflammatory disease involving these cell types. Recently we have elucidated the signaling pathway by which the CSF-1R regulates the suppression of the macrophage (M1) phenotype and enhances the trophic or repair (M2) phenotype. Current research is focused on CSF-1R signaling in monocytes, macrophages and osteoclasts, CSF-1R signaling mechanisms that regulate tumor associated macrophage enhancement of tumor progression and metastasis, PSTPIP2 action and the CSF-1R signaling deficits underlying the development of ALSP.
Signaling by the Shark tyrosine kinase: Embryonic dorsal closure in Drosophila is a series of morphogenetic movements involving the bilateral dorsal movement of the epidermis (cell stretching) and dorsal suturing of the leading edge cells to enclose the viscera. The Syk family tyrosine kinase, Shark, is expressed in the epidermis and plays a crucial role in this Jun kinase-dependent process where, with the adapter, Ddok, it acts upstream of JNK in leading edge cells. Shark is also expressed by glial cells, where it functions downstream of the Draper receptor and Src42A to regulate the recognition and engulfment of dying neuronal cells. Mutations in the genes for Shark-interacting proteins, coupled with cell biological approaches, are being used to define Shark function and the Shark signaling pathways.
Selected recent original work
Cecchini, M.G., Dominguez, M.G., Mocci, S., Wetterwald, A., Felix, R., Fleisch, H., Chisholm, O., Pollard, J.W., Hofstetter, W. and Stanley, E.R. (1994) Role of colony stimulating factor-1 in the establishment and regulation of tissue macrophages during post natal development of the mouse. Development 120:1357-1372. PMID: 8050349
Wang, Y., Yeung, Y.G., Langdon, W.Y. and Stanley, E.R. (1996) c-Cbl Is Transiently Tyrosine phosphorylated, Ubiquitinated, and Membrane-targeted following CSF-1 Stimulation of Macrophages. J. Biol. Chem. 271:17-20. PMID: 8550554
Yeung, Y.G., Soldera, S. and Stanley, E.R. (1998) A novel macrophage actin-associated protein (MAYP) is tyrosine phosphorylated following CSF-1 stimulation. J. Biol. Chem. 273:30638 30642. PMID: 9804836
Lee, P.S.W., Wang, Y., Dominguez, M.G., Yeung, Y-G., Murphy, M.A. Bowtell, D.D.L. and Stanley, E.R. (1999) The Cbl protooncoprotein stimulates CSF-1 receptor multiubiquitination and endocytosis, and attenuates macrophage proliferation. EMBO J. 18:3616-3628. PMID: PMC1171440
Fernandez, R., Takahashi, F., Liu, Z., Steward, R., Stein, D. and Stanley, E.R. (2000) The Drosophila Shark tyrosine kinase is required for embryonic dorsal closure. Genes and Development 14:604-614. PMID: PMC316420
Pixley, F.J., Lee, P.S.W., Condeelis, J. and Stanley, E.R. (2001) Protein tyrosine phosphatase phi regulates paxillin tyrosine phosphorylation and mediates Colony Stimulating Factor 1 induced morphological changes in macrophages. Mol. Cell. Biol. 21:1795-1809. PMID: PMC86738
Dai, X-M., Ryan, G.R., Hapel, A.J., Dominguez, M.G., Kapp, S., Sylvestre, V. and Stanley, E.R. (2002) Targeted disruption of the mouse CSF-1 receptor gene results in osteopetrosis, mononuclear phagocyte deficiency, increased splenic progenitor cell frequencies and reproductive defects. Blood 99:111-120. PMID: 11756160
Yeung, Y-G. and Stanley, E.R. (2003) Proteomic approaches to analysis of the early events in CSF-1 signal transduction. Molecular and Cellular Proteomics 2: 1143-1155. PMID: 12966146
Wyckoff, J., Wang, W., Lin, E.L., Wang, Y., Pixley, F.J., Stanley, E.R., Graf, T., Pollard, J.W., Segall, J. and Condeelis, J. (2004). A paracrine loop between tumor cells and macrophages is required for tumor cell migration in mammary tumors. Cancer Res. 64(19):7022-7029. PMID: 15466195
Dai X-M, Zong XH, Sylvestre V and Stanley ER. (2004) Incomplete restoration of colony stimulating factor-1 (CSF-1) function in CSF-1-deficient Csf1op/Csf1op mice by transgenic expression of cell surface CSF-1. Blood 103: 1114-1123. PMID: 14525772
Dai, X-M., Zong, X-H., Akhter, M.P. and Stanley, E.R. (2004). Osteoclast deficiency results in disorganized matrix, reduced mineralization, and abnormal osteoblast behavior in developing bone. J. Bone Min. Res. 19(9):1441-1451. PMID: 15312244
Chitu, V., Pixley, F.J., Yeung, Y.G., Macaluso, F., Condeelis, J and Stanley, E.R. (2005). The PCH family member MAYP/PSTPIP2 directly regulates F-actin bundling and enhances filopodia formation and motility in macrophages. Mol. Biol. Cell. 16(6):2947-2959. PMID: PMC1142438
Grosse, J., Chitu, V., Marquardt, A., Hanke, P., Schmittwolf, C., Zeitlmann, L., Schropp, P., Barth, B., Yu, P., Paffenholz, R., Stumm, G., Nehls M., and Stanley E. R. (2006). Mutation of mouse MAYP/PSTPIP2 causes a macrophage autoinflammatory disease. Blood 107(8):3350-3358. PMID: PMC1895761
Biswas, R., Stein, D. and Stanley, E.R (2006). Drosophila Dok is required for embryonic dorsal closure. Development 133(2):217-227. PMID: 16339186
Nandi, S., Akhter, M.P., Seifert, M.F., Dai, X-M. and Stanley, E.R. (2006). Developmental and functional significance of the CSF-1 proteoglycan chondroitin sulfate chain. Blood 107(2):786-795. PMID: PMC1895624
Zeigenfuss, J.S.*, Biswas, R.*, Avery, M.A., Sheehan, A.E., Hong, K., Yeung Y-G., Stanley, E.R.** and Freeman, M.R.** (2008). Draper-dependent glial phagocytic activity is mediated by Src and Syk family kinase signaling. Nature 453(7197):935-939. PMID: PMC2493287
Huynh, D., Dai, X-M., Nandi, S., Lightowler, S., Trivett, M., Chan, C-K., Bertoncello, I., Ramsay, R.G. and Stanley, E.R. (2009). CSF-1 dependence of Paneth cell development in the mouse small intestine. Gastroenterology 137(1):136-144. PMID: PMC2706482
Patsialou, A., Wyckoff, J., Wang, Y., Goswami, S., Stanley, E.R. and Condeelis J.S. (2009). Invasion of human breast cancer cells in vivo requires both paracrine and autocrine loops involving the colony stimulating factor-1 receptor. Cancer Research 69(24):9498-9506. PMID: PMC2794986
Xiong, Y., Song, D., Cai, Y., Yu, W., Yeung, Y.G., and Stanley, E.R. (2010). A CSF-1 receptor phosphotyrosine 559 signaling pathway regulates receptor ubiquitination and tyrosine phosphorylation. J. Biol. Chem. 286(2):952-960. PMID: PMC3020780
Wei, S., Nandi, S., Chitu, V., Yeung, Y-G., Yu, W., Huang, M., Williams, L.T., Lin, H. and Stanley, E.R. (2010). Functional overlap but differential expression of CSF-1 and IL-34 in their CSF-1 receptor-mediated regulation of myeloid cells. J Leukoc. Biol. 88(3):495-505. PMID: 20504948
Ginhoux, F., Greter, M., Leboeuf, M., Nandi, S., See, P., Gokhan, S., Mehler, M.F., Ng, L.G., Stanley, E.R., Samokhvalov, I.M. and Merad, M. (2010) Fate mapping studies reveal that adult microglia derive from primitive macrophages. Science 330(6005):841-845. PMID: 20966214
Sampaio, N., Yu, W., Cox, D., Wyckoff, J., Condeelis, J., Stanley, E.R. and Pixley, F.J. (2011). Phosphorylation of Y721 of the CSF-1R mediates PI3K association to regulate macrophage motility and enhancement of tumor cell invasion. J. Cell Sci. 124(Pt 12):2021-2031. PMID: PMC3104034
Yu, W., Chen, J., X. Ying, Pixley, F.J., Yeung, Y.G., and Stanley, E.R. (2012). Macrophage proliferation is regulated through CSF-1 receptor tyrosines 544, 559 and 807. J. Biol.Chem. 287:13694-704. PMID: 22375015.
Nandi, S., Gokhan,S., Dai, X-M., Wei, S., Enikolopov, G., Lin,H., Mehler, M.F. and Stanley E.R. (2012). The CSF-1 receptor ligands IL-34 and CSF-1 exhibit distinct developmental brain expression patterns and regulate neural progenitor cell maintenance and maturation. Developmental Biology 367:100-13. PMID: 22542597.
Chitu V., Nacu, V., Charles, J.F., Henne, W.M., McMahon, H.T., Nandi, S., Ketchum, H., Harris, R., Nakamura, M.C., Stanley, E.R. (2012) PSTPIP2 deficiency in mice causes osteopenia and increased differentiation of multipotent myeloid precursors into osteoclasts. Blood 120:3126-35. PMID: 22923495.
Nandi, S., Cioce, M., Yeung, Y.G., Nieves, E., Tesfa, L., Lin, H., Hsu, A.W., Halenbeck R., Cheng, H.Y., Gokhan, S., Mehler, M.F., Stanley, E.R.(2013).Receptor-type protein tyrosine phosphatase zeta is a functional receptor for interleukin-34. J. Biol. Chem. 288:21972-86. PMID: 23744080
Chitu, V., Gokhan, S., Gulinello, M., Branch C.A., Patil, M., Basu, R., Stoddart C., Mehler M.F. and Stanley E.R.(2014) Phenotypic characterization of a Csf1r haploinsuficient mouse model of adult-onset leukodystrophy with axonal spheroids and pigmented glia (ALSP). Neurobiology of Disease, 74C:219-228. PMID: 25497733
Chalmers, S.A., Chitu, V., Herlitz, L.C., Stanley, E.R. and Putterman, C. (2014). Macrophage depletion ameliorates nephritis induced by pathogenic antibodies. Journal of Autoimmunity, Dec 29. pii: S0896-8411(14)00171-1. doi: 10.1016/j.jaut.2014.11.007. [Epub ahead of print] PMID: 25554644.
Caescu, C.I., Guo,X., Tesfa, L., Bhagat, T.D., Verma, A., Zheng, D. and Stanley, E.R. (2015). Colony stimulating factor-1 receptor signaling networks inhibit mouse macrophage inflammatory responses by induction of microRNA-21. Blood, . Blood, 125:e1-13. PMID:25573988
Endele, M.,Loeffler, D.,Kokkaliaris, K.D.,Hilsenbeck, O.,Skylaki, S.,Hoppe, P.S.,Schambach, A.,Stanley, E.R.and Schroeder, T. (2017) M-CSF induced Src signaling can instruct monocytic lineage choice. Blood, Feb 3. pii: blood-2016-05-714329.PMID:28159742
Selected recent reviews
Pixley, F.J. and Stanley, E.R. (2004) CSF-1 Regulation of the Wandering Macrophage: Complexity in action. Trends in Cell Biol. 14:628-638. PMID: 15519852
Chitu, V. and Stanley E. R. (2006). Colony stimulating factor-1 in immunity and inflammation. Current Opinion in Immunology 18(1):39-48. PMID: 16337366
Chitu, V. and Stanley, E.R. (2007). Pombe Cdc15 homology (PCH) proteins: coordinators of membrane-cytoskeletal interactions. Trends in Cell Biol. 17(3):145-156. PMID: 17296299
Stanley, E.R. (2009), “Colony Stimulating Factor-1 Regulation of Macrophages in Development and Disease” in Gordon, S. ed.) Innate Immunity: Host recognition and response in health and disease, The Biomedical & Life Sciences Collection, Henry Stewart Talks Ltd. London (online at http://www.hstalks.com/bio).
Stanley, E.R. and Chitu, V. (2014). CSF-1 Receptor Signaling in Myeloid Cells. Cold Spring Harb Perspect Biol. 6(6):1-21 PMID: 24890514.
Chitu, V. and Stanley, E.R. (2015). CSF-1 Receptor. In: The PDGF Receptor Family. Chapter 10 of Receptor Tyrosine Kinases: Family and Subfamilies. (D.L. Wheeler and Yarden, Y., eds.), Humana Press, New York. pp 373-538.
Caescu, C.I. and Stanley, E.R. (2015). FLT3. In: The PDGF Receptor Family. Chapter 10 of Receptor Tyrosine Kinases: Family and Subfamilies. (D.L. Wheeler and Yarden, Y., eds.), Humana Press, New York. pp 373-538.
Chitu,V., Gokhan,S., Nandi, S., Mehler, M. and Stanley, E.R. (2016) Emerging roles for the CSF-1 receptor and its ligands in the nervous system. Trends in Neuroscience, 39:378-393.
Chitu,V. and Stanley, E.R. (2017) Regulation of embryonic and postnatal development by the CSF-1 receptor. Curr. Top. Dev. Biol. 123:229-275.
(last updated 3/15/17)
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More Information About Dr. E. Richard Stanley
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Albert Einstein College of Medicine
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