EGF-Induced Centrosome Separation Promotes Mitotic Progression and Cell Survival

Abstract

Timely and accurate assembly of the mitotic spindle is critical for the faithful segregation of chromosomes, and centrosome separation is a key step in this process. The timing of centrosome separation varies dramatically between cell types; however, the mechanisms responsible for these differences and its significance are unclear. Here, we show that activation of epidermal growth factor receptor (EGFR) signaling determines the timing of centrosome separation. Premature separation of centrosomes decreases the requirement for the major mitotic kinesin Eg5 for spindle assembly, accelerates mitosis, and decreases the rate of chromosome missegregation. Importantly, EGF stimulation impacts upon centrosome separation and mitotic progression to different degrees in different cell lines. Cells with high EGFR levels fail to arrest in mitosis upon Eg5 inhibition. This has important implications for cancer therapy because cells with high centrosomal response to EGF are more susceptible to combinatorial inhibition of EGFR and Eg5.

Separate to operate: control of centrosome positioning and separation

“…As the centrosomes separate further, more and more chromosomes become available to the MTs emanating from both poles, and this increases the chances of correct syntelic attachments due to symmetric outgrowth of MTs from both spindle poles [94]. In line with these observations and models [89,90,92,94,95], EGF-induced early centrosome separation promotes a faster mitotic progression with fewer chromosome segregation errors [92]. Induction of early centrosome separation either by addition of EGF to the medium or by expression of the EGFR decreases the requirement of Eg5 for mitotic progression [92].…”

“…Thirty years later, the biological outcome of this interesting observation was investigated in detail. Addition of EGF dissolves the centrosomal linker by increasing the local concentration of the upstream kinases Mst2 and Nek2 at the centrosomes, thus leading to premature centrosome separation [92]. Interestingly, this effect is cell type dependent since many cancer cells have a high degree of separated centrosomes due to elevated levels of EGF receptor (EGFR) expression.…”

Cancerous Inhibitor of Protein Phosphatase 2A (CIP2A) Protein Is Involved in Centrosome Separation through the Regulation of NIMA (Never In Mitosis Gene A)-related Kinase 2 (NEK2) Protein Activity

“…CIP2A Depletion Retards Centrosome Separation-Because centrosome separation occurs prior to mitosis and is a key step for the faithful segregation of chromosomes (50), and because the induction of active NEK2A induces premature centrosome splitting (38), the effect of CIP2A depletion on centrosome separation was examined. The protocol outlined in Fig.…”

Centrosomes at M phase act as a scaffold for the accumulation of intracellular ubiquitinated proteins

“…2 The centrosome is replicated between late G 1 and early S phases, whereupon it localizes to the spindle pole and participates in chromosome segregation during mitosis. 3,4 Polo-like kinase 1 (Plk1) and Aurora A are reportedly involved in centrosome maturation. 5,6 Plk1 phosphorylates pericentrin (PCNT), and phosphorylated PCNT recruits centrosomal proteins, such as CEP192, GCP-WD, Aurora A, and γ-tubulin, into centrosomes.…”