title: 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.
authors: Zentrum für Molekulare Biologie der Universität Heidelberg, DKFZ-ZMBH Allianz, Im Neuenheimer Feld 282, 69120 Heidelberg, Germany.
authors: Balca R
authors: BR
authors: Mardin
authors: Mayumi
authors: M
authors: Isokane
authors: Marco R
authors: MR
authors: Cosenza
authors: Alwin
authors: A
authors: Krämer
authors: Jan
authors: J
authors: Ellenberg
authors: Andrew M
authors: AM
authors: Fry
authors: Elmar
authors: E
authors: Schiebel
mesh_terms: D049109:Cell Proliferation; D002470:Cell Survival; D018385:Centrosome / Q000378:metabolism*; D003545:Cysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D004261:DNA Replication; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D066246:ErbB Receptors / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D016547:Kinesins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008938:Mitosis / Q000187:drug effects*; D000072379:NIMA-Related Kinases; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D059807:S Phase Cell Cycle Checkpoints; D000090742:Serine-Threonine Kinase 3; D015398:Signal Transduction; D008941:Spindle Apparatus / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D000099317:Hippo Kinases
chemical_list: D003545:Cysteine; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D016547:Kinesins; D000072379:NIMA-Related Kinases; D017346:Protein Serine-Threonine Kinases; D000090742:Serine-Threonine Kinase 3; C470243:KIF11 protein, human; C003724:3-tritylthio-L-alanine; C089441:NEK2 protein, human; C097835:STK3 protein, human; D000099317:Hippo Kinases
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