Abstract
Receptor tyrosine kinases (RTK) have long being studied with respect to the “canonical” signaling. This includes ligand-induced activation of a receptor tyrosine kinase at the cell surface that leads to receptor dimerization, followed by its phosphorylation in the intracellular domain and activation. The activated receptor then recruits cytoplasmic signaling molecules including other kinases. Activation of the downstream signaling cascade frequently leads to changes in gene expression following nuclear translocation of downstream targets. However, RTK themselves may localize within the nucleus, as either full-length molecules or cleaved fragments, with or without their ligands. Significant differences in this mechanism have been reported depending on the individual RTK, cellular context or disease. Accumulating evidences indicate that the colony-stimulating factor-1 receptor (CSF-1R) may localize within the nucleus. To date, however, little is known about the mechanism of CSF-1R nuclear shuttling, as well as the functional role of nuclear CSF-1R.
Similar content being viewed by others
References
Ancot F, Foveau B, Lefebvre J, Leroy C, Tulasne D (2009) Proteolytic cleavages give receptor tyrosine kinases the gift of ubiquity. Oncogene 28:2185–2195
Zhong W (2008) Going nuclear is again a winning (Wnt) strategy. Dev Cell 15:635–636. doi:10.1016/j.devcel.2008.10.012
Bray SJ (2006) Notch signalling: a simple pathway becomes complex. Nat Rev Mol Cell Biol 7(9):678–689
Chen BD, Lin HS, Hsu S (1983) Lipopolysaccharide inhibits the binding of colony-stimulating factor (CSF-1) to murine peritoneal exudate macrophages. J Immunol 130:2256–2260
Chen BD, Lin HS, Hsu S (1983) Tumor-promoting phorbol esters inhibit the binding of colony-stimulating factor (CSF-1) to murine peritoneal exudate macrophages. J Cell Physiol 116:207–212
Guilbert LJ, Stanley ER (1984) Modulation of receptors for the colony-stimulating factor, CSF-1, by bacterial lipopolysaccharide and CSF-1. J Immunol Methods 73:17–28
Downing JR, Roussel MF, Sherr CJ (1989) Ligand and protein kinase C down-modulate the colony-stimulating factor 1 receptor by independent mechanisms. Mol Cell Biol 9:2890–2896
Baccarini M, Dello Sbarba P, Buscher D, Bartocci A, Stanley ER (1992) IFN-gamma/lipopolysaccharide activation of macrophages is associated with protein kinase C-dependent down-modulation of the colony-stimulating factor-1 receptor. J Immunol 149:2656–2661
Glenn G, van der Geer P (2007) CSF-1 and TPA stimulate independent pathways leading to lysosomal degradation or regulated intramembrane proteolysis of the CSF-1 receptor. FEBS Lett 581:5377–5381
Glenn G, van der Geer P (2008) Toll-like receptors stimulate regulated intramembrane proteolysis of the CSF-1 receptor through Erk activation. FEBS Lett 582:911–915
Dello Sbarba P, Rovida E, Caciagli B, Nencioni L, Labardi D, Paccagnini A, Savini L, Cipolleschi MG (1996) Interleukin-4 rapidly down-modulates the macrophage colony-stimulating factor receptor in murine macrophages. J Leukoc Biol 60:644–650
Dello Sbarba P, Nencioni L, Labardi D, Rovida E, Caciagli B, Cipolleschi MG (1996) Interleukin 2 down-modulates the macrophage colony-stimulating factor receptor in murine macrophages. Cytokine 8:488–494
Dello Sbarba P, Rovida E (2002) Transmodulation of cell surface regulatory molecules via ectodomain shedding. Biol Chem 383:69–83
Rovida E, Paccagnini A, Del Rosso M, Peschon J, Dello Sbarba P (2001) TNF-alpha-converting enzyme cleaves the macrophage colony-stimulating factor receptor in macrophages undergoing activation. J Immunol 166:1583–1589
Caescu CI, Jeschke GR, Turk BE (2009) Active-site determinants of substrate recognition by the metalloproteinases TACE and ADAM10. Biochem J 424(1):79–88. doi:10.1042/BJ20090549
Horiuchi K (2013) A brief history of tumor necrosis factor α-converting enzyme: an overview of ectodomain shedding. Keio J Med 62(1):29–36
Sherr CJ (1990) Colony-stimulating factor-1 receptor. Blood 75(1):1–12
Wilhelmsen K, van der Geer P (2004) Phorbol 12-myristate 13-acetate-induced release of the colony-stimulating factor 1 receptor cytoplasmic domain into the cytosol involves two separate cleavage events. Mol Cell Biol 24:454–464
Carpenter G (2003) Nuclear localization and possible functions of receptor tyrosine kinases. Curr Opin Cell Biol 15(2):143–148
Carpenter G, Liao HJ (2013) Receptor tyrosine kinases in the nucleus. Cold Spring Harb Perspect Biol 5:a008979
Barbetti V, Morandi A, Tusa I, Digiacomo G, Riverso M, Marzi I, Cipolleschi MG, Bessi S, Giannini A, Di Leo A, Dello Sbarba P, Rovida E (2013) Chromatin-associated CSF-1R binds to the promoter of proliferation-related genes in breast cancer cells. Oncogene. doi:10.1038/onc.2013.542
Wells A, Marti U (2002) Signalling shortcuts: cell-surface receptors in the nucleus? Nat Rev Mol Cell Biol 3(9):697–702
Bryant DM, Stow JL (2005) Nuclear translocation of cell-surface receptors: lessons from fibroblast growth factor. Traffic 6:947–954
Zwaenepoel O, Tzenaki N, Vergetaki A, Makrigiannakis A, Vanhaesebroeck B, Papakonstanti EA (2012) Functional CSF-1 receptors are located at the nuclear envelope and activated via the p110δ isoform of PI 3-kinase. FASEB J 26:691–706
Wanner G, Mayer C, Kehlbach R, Rodemann HP, Dittmann K (2008) Activation of protein kinase Cepsilon stimulates DNA-repair via epidermal growth factor receptor nuclear accumulation. Radiother Oncol 86:383–390
Scholl SM, Pallud C, Beuvon F, Hacene K, Stanley ER, Rohrschneider L, Tang R, Pouillart P, Lidereau R (1994) Anti-colony-stimulating factor-1 antibody staining in primary breast adenocarcinomas correlates with marked inflammatory cell infiltrates and prognosis. J Natl Cancer Inst 86(2):120–126
Lin H, Lee E, Hestir K, Leo C, Huang M, Bosch E et al (2008) Discovery of a cytokine and its receptor by functional screening of the extracellular proteome. Science 320:807–811
Mancini A, Koch A, Whetton AD, Tamura T (2004) The M-CSF receptor substrate and interacting protein FMIP is governed in its subcellular localization by protein kinase C-mediated phosphorylation, and thereby potentiates M-CSF-mediated differentiation. Oncogene 23:6581–6589
Morandi A, Barbetti V, Riverso M, Dello Sbarba P, Rovida E (2011) The colony-stimulating factor-1 (CSF-1) receptor sustains ERK1/2 activation and proliferation in breast cancer cell lines. PLoS One 6:e27450
Hammes LS, Tekmal RR, Naud P, Edelweiss MI, Kirma N, Valente PT, Syrjänen KJ, Cunha-Filho JS (2008) Up-regulation of VEGF, c-fms and COX-2 expression correlates with severity of cervical cancer precursor (CIN) lesions and invasive disease. Gynecol Oncol 110(3):445–451. doi:10.1016/j.ygyno.2008.04.038
Li NF, Kocher HM, Salako MA, Obermueller E, Sandle J, Balkwill F (2009) A novel function of colony-stimulating factor 1 receptor in hTERT immortalization of human epithelial cells. Oncogene 28:773–780
Dittmann K, Mayer C, Rodemann HP (2010) Nuclear EGFR as novel therapeutic target: insights into nuclear translocation and function. Strahlenther Onkol 186(1):1–6. doi:10.1007/s00066-009-2026-4
Acknowledgments
This work was supported by Associazione Italiana per la Ricerca sul Cancro, Istituto Toscano Tumori, Ministero della Salute, Regione Toscana, Fondazione Cassa di Risparmio di Volterra, Fondazione Oretta Bartolomei-Corsi.
Conflict of interest
The authors have no conflict of interest to disclose.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Rovida, E., Dello Sbarba, P. Possible mechanisms and function of nuclear trafficking of the colony-stimulating factor-1 receptor. Cell. Mol. Life Sci. 71, 3627–3631 (2014). https://doi.org/10.1007/s00018-014-1668-2
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00018-014-1668-2