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Proc Natl Acad Sci U S A. 2017 Dec 12;114(50):E10687-E10696. doi: 10.1073/pnas.1705682114. Epub 2017 Nov 21.

EB1-binding-myomegalin protein complex promotes centrosomal microtubules functions.

Author information

1
Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM, Institut Paoli-Calmettes, CNRS, Aix-Marseille Université,13009 Marseille, France.
2
Laboratoire de Spectrométrie de Masse BioOrganique, CNRS, Institut Pluridisciplinaire Hubert Curien UMR 7178, Université de Strasbourg, 67087 Strasbourg, France.
3
Department of Bioengineering, Graduate School of Engineering, Osaka City University, Osaka 558-8585, Japan.
4
Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM, Institut Paoli-Calmettes, CNRS, Aix-Marseille Université,13009 Marseille, France; pascal.verdier-pinard@inserm.fr ali.badache@inserm.fr.

Abstract

Control of microtubule dynamics underlies several fundamental processes such as cell polarity, cell division, and cell motility. To gain insights into the mechanisms that control microtubule dynamics during cell motility, we investigated the interactome of the microtubule plus-end-binding protein end-binding 1 (EB1). Via molecular mapping and cross-linking mass spectrometry we identified and characterized a large complex associating a specific isoform of myomegalin termed "SMYLE" (for short myomegalin-like EB1 binding protein), the PKA scaffolding protein AKAP9, and the pericentrosomal protein CDK5RAP2. SMYLE was associated through an evolutionarily conserved N-terminal domain with AKAP9, which in turn was anchored at the centrosome via CDK5RAP2. SMYLE connected the pericentrosomal complex to the microtubule-nucleating complex (γ-TuRC) via Galectin-3-binding protein. SMYLE associated with nascent centrosomal microtubules to promote microtubule assembly and acetylation. Disruption of SMYLE interaction with EB1 or AKAP9 prevented microtubule nucleation and their stabilization at the leading edge of migrating cells. In addition, SMYLE depletion led to defective astral microtubules and abnormal orientation of the mitotic spindle and triggered G1 cell-cycle arrest, which might be due to defective centrosome integrity. As a consequence, SMYLE loss of function had a profound impact on tumor cell motility and proliferation, suggesting that SMYLE might be an important player in tumor progression.

KEYWORDS:

cell motility; centrosome; microtubules; mitotic spindle

PMID:
29162697
PMCID:
PMC5740655
DOI:
10.1073/pnas.1705682114
[Indexed for MEDLINE]
Free PMC Article

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