4E-BP1 participates in maintaining spindle integrity and genomic stability via interacting with PLK1

Abstract

The essential function of eIF4E-binding protein 1 (4E-BP1) in translation initiation has been well established; however, the role of 4E-BP1 in normal cell cycle progression is coming to attention. Here, we revealed the role of 4E-BP1 on mitotic regulation and chromosomal DNA dynamics during mitosis. First, we have observed the co-localization of the phosphorylated 4E-BP1 at T37/46 with Polo-like kinase 1 (PLK1) at the centrosomes during. Depression of 4E-BP1 by small interfering RNA in HepG2 or HeLa cells resulted in an increased outcome of polyploidy and aberrant mitosis, including chromosomal DNA misaligned and multi-polar spindles or multiple centrosomes. We observed that 4E-BP1 interacted with PLK1 directly in vitro and in vivo in mitotic cells, and the C-terminal aa 77-118 of 4E-BP1 mediates its interaction with PLK1. PLK1 can phosphorylate 4E-BP1 in vitro. Furthermore, the depletion of 4E-BP1 sensitized HepG2 and HeLa cells to the microtubule disruption agent paclitaxel. These results demonstrate that 4E-BP1, beyond its role in translation regulation, can function as a regulator of mitosis via interacting with PLK1, and possibly plays a role in genomic stability maintaining.

Mitotic protein kinase CDK1 phosphorylation of mRNA translation regulator 4E-BP1 Ser83 may contribute to cell transformation

“…We were also able to localize a portion of S83-phosphorylated 4E-BP1 at the centrosomes consistent with a previous report, which shows that 4E-BP1 knockdown leads to multipolar spindles and misaligned chromosomes (23). Further, S83 phosphorylation increased from prophase to metaphase and decreased thereafter, which is in agreement with nocodazole prometaphase synchronization results and with the timing of CDK1 activity (27).…”

“…Resistance of various cancers to mTOR inhibitor treatment indicates that other pathways are implicated in 4E-BP1 inactivation (14). Several serine/threonine kinases have been shown to phosphorylate 4E-BP1, such as p38 MAPK, ERK, PIM2, ATM, CDK1, PLK1, LRRK2, GSK3β, and CK1e (15)(16)(17)(18)(19)(20)(21)(22)(23). We recently demonstrated that cyclin-dependent kinase 1 (CDK1) phosphorylates 4E-BP1 at canonical sites T37, T46, S65, and T70 during mitosis and generates a high-molecularweight phospho-isoform called δ-4E-BP1, even in the absence of mTOR activity (24).…”

Therapeutic Innovations for Targeting Hepatoblastoma

“…For instance, phosphorylation of 4EBP1 at these two distinct sites can be performed by CDK1 under conditions of reduced mTOR signaling (115). Likewise, PLK1 was shown to have similar effects in HepG2 (116). Furthermore, our data also indicated an increase in phosphorylation of mTOR at S2448, which, in this form, is known to be associated with mTORC1 complex (117) (Figure 1).…”

Association of Maternal mRNA and Phosphorylated EIF4EBP1 Variants With the Spindle in Mouse Oocytes: Localized Translational Control Supporting Female Meiosis in Mammals

“…Kinases associated with the spindle and cell cycle progression are obvious likely controllers. Kinases implicated in EIF4EBP1 phosphorylation include mTOR, polo-like kinases, cyclin-dependent cell division kinases, and several others (Lawrence et al 1997;Yang and Kastan 2000;Heesom et al 2001;Shang et al 2012). For example, PLK1-mediated phosphorylation in the region of human EIF4EBP1 residues 77-118, which includes Ser112, is accompanied by localization to spindles in mitotic cells.…”