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Research

What we do (if you are not a biological scientist): we study how cells are wired: how different systems similar to wires and switches control the elements that make up a cell by transmitting signals and changing the behavior, location or amount of these elements (we like to say that we study signal transduction). More specifically we are interested in understanding how a particular type of signal (protein phosphorylation) is involved in controlling how cells divide. (Applications? you may want to know that aberrant control of cell division is at the very heart of, for example, cancer)

HeLa division

Human HeLa cell dividing (ß-tubluin in green, DNA in blue; Images: Sara Sdelci).

Background:

Mitosis is a highly controlled biological process. A variety of signals regulate multiple elements both in time and space to ensure that chromosomes are segregated in two equal groups into daughter cells. Cells prepare for mitosis in G2, and in response to CDK1 activation undergo different changes, including the reorganization of the microtubule apparatus to build the mitotic spindle. Failure to properly control spindle formation and chromosome segregation may result in aneuploidy, one of the most frequent features of cancer cells.

We study how protein phosphorylation, alongside other signals such as ubiquitination or the Ran(GTP) gradient, control progression through mitosis and the formation of the mitotic spindle (see for example Walczak and Heald 2008) through the modification of different protein types, for example proteins that control the growth or disposition of the microtubules. These proteins often accumulate at the centrosome, the main microtubule organizing center of animal cells. The centrosome is a cytoplasmic non-membranous organelle that contains two microtubule-based cylinders (the centrioles) surrounded by a structured cloud of protein (the pericentriolar material or PCM). When present (e.g. in animal cells) the centrosome is the major place of novel microtubule nucleation (see Teixidó-Travesa et al 2012) and organization, playing a key role during spindle formation. Centrosomes also have a major role in establishing cell polarity and enabling asymmetrical division (e.g. in stem cells) as well as during cilia formation (Bornens 2012).

Prophase_s

Centrosomes (visualized by γ-tubulin staining in red; DNA in blue) in a prophase HeLa cell (left) as compared to interphase cells (right).
Note size and separation of duplicated centrosomes in prophase. Image: Sara Sdelci.

NIMA family kinases, the Neks:

Of the different families of enzymes controlling spindle formation and mitotic progression, one of the least studied is the NIMA family of protein kinases. The NIMA family comprises 11 members (Nek1-11) in mammals (see O’Connell et al. 2003). Of these, Nek2 is involved in the regulation of the centrosome cycle in G2, while Nek9 and the highly similar Nek6 and Nek7 are after our work known to form a signaling module that is crucial for the normal formation of the mitotic spindle (see below, and Fry et al. 2012 for a recent review on cell cycle regulation by Neks).

Nek9, Nek6 and Nek7:

Nek9 is a 120 kDa NIMA kinase that contains an autoinhibitory RCC1 domain followed by a C-terminal tail that functions as an oligomerization domain and binds among other proteins to the related Nek6 and Nek7.

Human Nek9, Nek6 and Nek7.

Human Nek9, Nek6 and Nek7.

We have shown that a small fraction of Nek9 is activated during mitosis at the centrosomes by a mechanism involving phosphorylation by two of the major mitotic regulators, CDK1 and Plk1 (Bertran et al 2011). Once active, Nek9 autophosphorylates and is able to bind and activate Nek6/7.

Nek9, Nek6 and Nek7 have been shown by us and others to be necessary for normal spindle formation. We presently study the molecular basis of this and have found that, downstream of Nek9, Nek6/7 control centrosome separation during early mitosis through the regulation of the centrosomal accumulation of Eg5, a molecular motor of the kinesin family that is crucial for bipolar spindle formation (Rapley et al. 2008Bertran et al 2011; for a review on Eg5 see Ferenz et al. 2012). In collaboration with the Vernos group at the CRG, we have also shown that simultaneously Nek9 controls the ability of the centrosomes to nucleate novel microtubules by regulating the centrosomal accumulation of Nedd1/GCP-WD, an adaptor for the microtubule nuceating complex γ-TuRC (Sdelci et al. 2012; for an overview on nucleation see Teixidó-Travesa et al 2012).

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