Functional CSF-1 receptors are located at the nuclear envelope and activated via the p110δ isoform of PI 3-kinase

• Published in: The FASEB journal Vol. 26; no. 2; p. 691
• Main Authors: Zwaenepoel, Olivier, Tzenaki, Niki, Vergetaki, Aikaterini, Makrigiannakis, Antonis, Vanhaesebroeck, Bart, Papakonstanti, Evangelia A
• Format: Journal Article
• Language: English
• Published: United States 01.02.2012
• Subjects: Animals; Breast Neoplasms - metabolism; Cell Line; Cell Line, Tumor; Class I Phosphatidylinositol 3-Kinases; Cyclin-Dependent Kinase Inhibitor p27 - metabolism; Female; Humans; Macrophage Colony-Stimulating Factor - metabolism; Macrophage Colony-Stimulating Factor - pharmacology; Macrophages - metabolism; Mice; Mice, Knockout; Nuclear Envelope - metabolism; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; Proto-Oncogene Proteins c-akt - metabolism; rab5 GTP-Binding Proteins - antagonists & inhibitors; rab5 GTP-Binding Proteins - genetics; rab5 GTP-Binding Proteins - metabolism; Receptor, Macrophage Colony-Stimulating Factor - metabolism; RNA, Small Interfering - genetics; Signal Transduction
• ISSN: 1530-6860
• DOI: 10.1096/fj.11-189753

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.