title: Functional CSF-1 receptors are located at the nuclear envelope and activated via the p110δ isoform of PI 3-kinase.
abstract: Colony stimulating factor-1 (CSF-1) and its receptor (CSF-1R) are key regulators of macrophage biology, and their elevated expression in cancer cells has been linked to poor prognosis. CSF-1Rs are thought to function at the plasma membrane. We show here that functional CSF-1Rs are present at the nuclear envelope of various cell types, including primary macrophages, human cancer cell lines, and primary human carcinomas. In response to CSF-1, added to intact cells or isolated nuclei, nucleus-associated CSF-1R became phosphorylated and triggered the phosphorylation of Akt and p27 inside the nucleus. Extracellularly added CSF-1 was also found to colocalize with nucleus-associated CSF-1Rs. All these activities were found to depend selectively on the activity of the p110δ isoform of phosphoinositide 3-kinase (PI3K). This finding was related to the p110δ-dependent translocation of exogenous CSF-1 to the nucleus-associated CSF-1Rs, correlating with a prominent role of p110δ in activation of the Rab5 GTPase, a key regulator of the endocytic trafficking. siRNA-silencing of Rab5a phenocopied p110δ inactivation and nuclear CSF-1 signaling. Our work demonstrates for the first time the presence of functional nucleus-associated CSF-1Rs, which are activated by extracellular CSF-1 by a mechanism that involves p110δ and Rab5 activity. These findings may have important implications in cancer development.
authors.affiliation: Department of Biochemistry, School of Medicine, University of Crete, Heraklion, Greece.
authors.forename: Olivier
authors.initials: O
authors.lastname: Zwaenepoel
authors.forename: Niki
authors.initials: N
authors.lastname: Tzenaki
authors.forename: Aikaterini
authors.initials: A
authors.lastname: Vergetaki
authors.forename: Antonis
authors.initials: A
authors.lastname: Makrigiannakis
authors.forename: Bart
authors.initials: B
authors.lastname: Vanhaesebroeck
authors.forename: Evangelia A
authors.initials: EA
authors.lastname: Papakonstanti
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D005260:Female; D006801:Humans; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009685:Nuclear Envelope / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D015398:Signal Transduction; D020696:rab5 GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016173:Macrophage Colony-Stimulating Factor; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D016186:Receptor, Macrophage Colony-Stimulating Factor; D020696:rab5 GTP-Binding Proteins; C486018:PIK3CD protein, human; C421683:Pik3cd protein, mouse