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Analysis of RAS mediated signal transduction cascades

  • Full or part time
  • Application Deadline
    Applications accepted all year round
  • Self-Funded PhD Students Only
    Self-Funded PhD Students Only

About This PhD Project

Project Description

The Ras proteins are widely conserved and they regulate signalling pathways that control cellular growth and differentiation. Most importantly, mutations in RAS genes are frequently associated with human cancers. Despite extensive research to uncover the molecular nature of Ras proteins, the means by which Ras-mediated signal transduction cascades are integrated in cells still requires further rigorous studies. Active RAS proteins interact with a number of target molecules to transduce a variety of different signals. Also, de-sensitisation or negative feedback mechanisms operate in concert with the signalling processes to make the signals to be temporal and specific.

We employ a genetically tractable model organism, the fission yeast. In this organism, mating pheromone triggers the RAS-MAPK signaling pathway essential for meiotic differentiation. It also induces dramatic morphological change of the cells leading to mating, a cell fusion event between cells of opposite mating types. The system is ideal to dissect the mechanisms by which the RAS-MAPK signal activation is regulated and highlight basic regulatory concepts of RAS protein signalling.
We aim to evaluate the role of Ras1 in coordinating both MAPKSpk1 activation due to pheromone signalling and activation of the Cdc42 pathway responsible for actin reorganisation.

Both constitutive activation of RAS or MAPK disturbs meiotic differentiation. Intriguingly, however, they give different phenotypes. Thus, fine-tuning of the signalling is expected to be crucial for the concerted signal transduction. This project will generate various mutants in the RAS and MAP kinase cascades in order to analyse spatial and temporal regulation of the signaling events.



We are an equal opportunities employer and particularly welcome applications for Ph.D. places from women, minority ethnic and other under-represented groups.

References

1.Dhani DK, Goult BT, George GM, Rogerson DT, Bitton DA, Dinsdale D, Miller CJ, Schwabe JW, Tanaka K. 2013. Mzt1/Tam4, a fission yeast MOZART1 homologue, is an essential component of the γ-tubulin complex and directly interacts with GCP3Alp6. Mol Biol Cell, [Epub ahead of print]
2.Funaya C, Samarasinghe S, Pruggnaller S, Ohta M, Connolly Y, Müller J, Murakami H, Grallert A, Yamamoto M, Smith D, Antony C, Tanaka K. 2012. Transient structure associated with the spindle pole body directs meiotic microtubule reorganization in S.pombe. Curr. Biol., 22, 562-574.
3.Tanaka, K., Kohda, T., Yamashita, A., Nonaka, N. and Yamamoto, M. 2005. Hrs1p/Mcp6p on the meiotic SPB organizes astral microtubule arrays for oscillatory nuclear movement. Curr. Biol., 15, 1479-1486.
4.Hirota, K., Tanaka, K., Ohta, K. and Yamamoto, M. 2003. Gef1p and Scd1p, the Two GDP-GTP exhange factors for Cdc42p, form a ring structure that shrinks during cytokinesis in Schizosaccharomyces pombe. Mol. Biol. Cell, 14, 3617-3627.


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