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Joan Roig: Cell Cycle and Signaling

@ + ATP ⇄ @-P + ADP

Lab Presentation

We are interested in understanding how cell division is controlled, and more specifically how before and during mitosis a number of signaling modules reorganize cellular elements with the objective of building the spindle and correctly segregating the duplicated chromosomes into two daughter cells (evidently quite an important process -think cell death, disease and mayhem in general if things go wrong with it). The microtubule cytoskeleton, associated proteins including molecular motors and the centrosomes (in animal cells) are central to this and thus we pay special attention to them.

We are focused on studying the NIMA-family kinases Nek9, Nek6 and Nek7. We have shown that during G2/M Nek9 is activated at centrosomes and then it binds and activates the highly similar Nek6 and Nek7. Once active the three kinases can modify different substrates, controlling their localization and/or function. We use genetically modified cells and animals to investigate the importance of this for both centrosome and spindle function. 

Research Lines

Known and novel functions of the Nek9/Nek6/7 module.
We would like to understand the functions of the Nek9/Nek6/7 module in different cell types and physiopathological contexts. For this we use different interfering techniques in both cells and organisms and seek to enumerate the substrates of the kinases using high throughput proteomic techniques combined with more classical approaches. The final objective is to understand how phosphorylation by Nek9 or Nek6/7 affect substrate behavior and how this is used by the cell to perform different tasks. An example of this would be the phosphorylation of the molecular motor Eg5 by Nek6/7, that through the interaction with a number of proteins results in Eg5 accumulation around centrosomes and makes posible the separation of these organelles at the beginning of mitosis and thus the rapid and accurate segregation of chromosomes to daughter cells.
Nek9, Nek6 and Nek7 in pathological states.
We investigate the possible implication of Nek9, Nek6 and Nek7 in cellular transformation and cancer onset as well as their interest as targets of antimitotic treatments.
Phosphorylation and signaling in G2 and M
We are especially interested in understanding how phosphorylation modulates the action of other signaling systems during G2/M and the organization of the mitotic spindle.
Joan Roig Amorós
  • Joan Roig
  • IBMB-CSIC
  • Baldiri i Reixac, 10-12
  • 08028 Barcelona, Spain
  • Phone: +34 934039679
  • E-mail: joan.roig@ibmb.csic.es

Principal Investigator



Past students


Present:

  • Joan Roig, group leader.
  • Paula Martínez, PhD student.
  • Núria Gallisà, PhD student.
  • Marta Redondo, Master Student
  • Núria Campos, Lab Manager.

Past:

  • Bruna Frielink Immich, PhD student.
    Now finishing her PhD student at the UFRGS, in Porto Alegre, Brazil.  
  • Susana Eibes, PhD student.
    PhD Univ. of Barcelona, 2016 "Functional study of the NIMA Protein Kinases Nek9, Nek6 and Nek7 at the onset of mitosis".
    Present location: Danish Cancer Society Research Center, Copenhagen, Denmark.
  • Cristina Vila, lab manager.
    Present location: Esteve, Barcelona.
  • Sara Sdelci, PhD student.
    PhD Univ. of Barcelona, 2012 ” Role of the kinases Nek6, Nek7 and Nak9 in the regulation of the centrosome cycle”.
    Present location: CeMM, Vienna, Austria.
  • Neus Teixidó, postdoctoral fellow.
    Present location: Thomson Reuters, Barcelona.
  • M. Teresa Bertran, PhD student.
    PhD Univ. of Barcelona, 2012 “Study of the phosphorylation and activation of the protein kinase Nek9 during mitosis”.
    Present location: London Research Intitute, London, UK.
  • Laura Regué, PhD student.
    PhD Univ. of Barcelona, 2011 ” Molecular basis of the regulation of the activity of the Nercc1/Nek9 protein kinase”.
    Present location: MGH/HMS, Harvard University, Boston, USA.
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).

Articles:

  • Cota, R.R., Teixidó-Travesa, N., Ezquerra, A., Eibes, S., Lacasa, C., Roig, J. and Lüders, J. (2016) MZT1 regulates microtubule nucleation by linking γTuRC assembly to adapter-mediated targeting and activation. J. Cell. Sci.  jcs.195321. [Epub ahead of print]. Pubmed
  • Haq, T., Richards, M.W., Burgess, S.G., Gallego, P., Yeoh, S., O'Regan, L., Reverter, D., Roig, J., Fry, A.M. and Bayliss, R. (2105) Mechanistic basis of Nek7 activation through Nek9 binding and induced dimerization. Nat. Commun. 2, 6:8771. PubMed
  • Januschke, J., Reina, J., Llamazares, S., Bertran, T., Rossi, F., Roig, J. and Gonzalez, C. (2013) Centrobin controls mother-daughter centriole asymmetry in Drosophila neuroblasts. Nat. Cell. Biol., 15, 241-8. PubMed
  • Gallego, P., Velazquez-Campoy, A., Regue, L., Roig, J. and Reverter, D. (2013) Structural analysis of the regulation of the DYNLL/LC8 binding to Nek9 by phosphorylation. J. Biol. Chem. 288, 12283-12294. PubMed (featured in the ALBA Synchrotron and IRB pages)
  • Sdelci, S., Schutz, M., Pinyol, R., Bertran, M.T., Regué, L., Caelles, C. Vernos, I. and Roig, J. (2012). Nek9 phosphorylation of NEDD1/GCP-WD contributes to Plk1 control of γ-tubulin recruitment to the mitotic centrosome. Curr. Biol. 22, 1516-1523. PubMed (Artículo del mes, Spanish Society of Biochemistry and Molecular Biology, SEBBM)
  • Bertran, M.T., Sdelci, S., Regué, L., Avruch, J., Caelles, C. and Roig, J. (2011). Nek9 is a Plk1-activated kinase that controls early centrosome separation through Nek6/7 and Eg5. EMBO J. 30, 263-2647. PubMed (Featured in Cell Cycle, see below)
  • Regué, L., Sdelci, S., Bertran, M.T., Caelles, C., Reverter, D. and Roig, J. (2011). DYNLL/LC8 controls signal transduction through the Nek9/Nek6 signaling module by regulating Nek6 binding to Nek9. J. Biol. Chem. 286, 18118-18129. PubMed
  • Teixidó-Travesa, N., Villén, J., Lacasa, C., Bertran, M.T., Archinti, M., Gygi, S., Caelles, C., Roig, J. and Jens Lüders (2010). The γTuRC revisited: a comparative analysis of interphase and mitotic human γTuRC re-defines the set of core components and identifies the novel subunit GCP8. Mol. Biol. Cell. 21, 3963-3972. PubMed
  • Rapley, J., Nicolàs, M., Groen, A., Regué, L., Bertran, M.T., Caelles, C., Avruch, J. and Roig, J. (2008). The NIMA-family kinase Nek6 phosphorylates the kinesin Eg5 at a novel site necessary for mitotic spindle formation. J. Cell Sci. 121, 3912-21. PubMed

Comments, Reviews and Book Chapters:

  • Eibes, S. and Roig, J. (2016) MCRS1: Not only ran. Cell Cycle. 15, 2693-4. Pubmed 
  • Teixidó-Travesa, N., Roig, J. and Lüders, J. (2012) The where, when and how of microtubule nucleation – one ring to rule them all. J Cell Sci 125: 4445-4456.  PubMed
  • Sdelci, S., Bertran, M.T. and Roig, J. (2011) Nek9, Nek6, Nek7 and the separation of centrosomes. Cell Cycle. 10, 3816-7.  PubMed
  • Roig, J. (2010). Nek6. UCSD-Nature Molecule Pages. doi:10.1038/mp.a003029.01.  Link
  • Roig, J. (2010). Nek7. UCSD-Nature Molecule Pages. doi:10.1038/mp.a003428.01.  Link
  • Roig, J. (2010). Nek9. UCSD-Nature Molecule Pages. doi:10.1038/mp.a003631.01.  Link

We are looking for new members of the lab. If you are considering a PhD or a Postdoc in Barcelona, or willing to do the Master experimental work studying cell division and signal transduction (yes, it is related to cancer), please contact us!

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