title: Eribulin disrupts EB1-microtubule plus-tip complex formation.
abstract: Abstract Eribulin mesylate is a synthetic analog of halichondrin B known to bind tubulin and microtubules, specifically at their protein rich plus-ends, thereby dampening microtubule (MT) dynamics, arresting cells in mitosis, and inducing apoptosis. The proteins which bind to the MT plus-end are known as microtubule plus-end tracking proteins (+TIPs) and have been shown to promote MT growth and stabilization. Eribulin's plus-end binding suggests it may compete for binding sites with known +TIP proteins such as End-binding 1 (EB1). To better understand the impact of eribulin plus-end binding in regard to the proteins which normally bind there, cells expressing GFP-EB1 were treated with various concentrations of eribulin. In a concentration dependent manner, GFP-EB1 became dissociated from the MT plus-ends following drug addition. Similar results were found with immuno-stained fixed cells. Cells treated with low concentrations of eribulin also showed decreased ability to migrate, suggesting the decrease in MT dynamics may have a downstream effect. Extended exposure of eribulin to cells leads to total depolymerization of the MT array. Taken together, these data show eribulin effectively disrupts EB1 +TIP complex formation, providing mechanistic insights into the impact of eribulin on MT dynamics.
authors.affiliation: a Department of Physiology and Biophysics ; Albert Einstein College of Medicine ; Bronx , NY USA.
authors.forename: Brian
authors.initials: B
authors.lastname: O'Rourke
authors.forename: Chia-Ping Huang
authors.initials: CP
authors.lastname: Yang
authors.forename: David
authors.initials: D
authors.lastname: Sharp
authors.forename: Susan Band
authors.initials: SB
authors.lastname: Horwitz
mesh_terms: D045744:Cell Line, Tumor; D005663:Furans / Q000378:metabolism*; D006801:Humans; D007659:Ketones / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008870:Microtubules / Q000378:metabolism*; D014404:Tubulin / Q000378:metabolism; D000095662:Polyether Polyketides
chemical_list: D005663:Furans; D007659:Ketones; D008869:Microtubule-Associated Proteins; D014404:Tubulin; C500985:MAPRE1 protein, human; C490954:eribulin; D000095662:Polyether Polyketides
keywords: +TIP, plus-end tracking protein; EB, end binding; EB1; MT, microtubule; eribulin; microtubules; migration; taxol