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Unravelling the roles of components that regulate protein phosphorylation and ubiquitylation pathways emerging from the genetic analysis of human disease.

  • Full or part time
    Prof Alessi
  • Application Deadline
    Applications accepted all year round
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

My laboratory focuses on unravelling the roles of components that regulate protein phosphorylation and ubiquitylation pathways emerging from the genetic analysis of human disease. The aim of our work is to discover how these pathways are organised, how they recognise signals, how the signal moves down the pathway to elicit physiological responses and to comprehend what goes wrong in human disease. We hope that these findings will enable us to play the engineer in devising new strategies to treat disease. Wherever possible, we will work closely with pharmaceutical companies, as well as chemical biologists, to help with the development of tool compounds that specifically inhibit the signalling components with which we are working. In combination with genetic approaches, these tool compounds will be very powerful in helping us to decipher the physiological roles of signalling pathways and in validating to what extent inhibiting these networks effectively suppresses disease.

Funding Notes

We offer a 4 year studentship in which you would join a particular lab in the Unit. However, we strongly encourage prospective students to become part of the 4-year PhD programme in which you carry out rotation projects in two labs within the Unit (View Website). This studentship is jointly funded by the Medical Research Council and the University of Dundee and carries a tax-free stipend of £20,000 per annum

References

1 Bago, R., et al. (2014) Characterization of VPS34-IN1, a selective inhibitor of Vps34, reveals that the phosphatidylinositol 3-phosphate-binding SGK3 protein kinase is a downstream target of class III phosphoinositide 3-kinase. Biochem J. 463, 413-427
2 Sommer, E. M., et al (2013) Elevated SGK1 predicts resistance of breast cancer cells to Akt inhibitors. Biochem J. 452, 499-508
3 Ritorto, M. S., et al. (2014) Screening of DUB activity and specificity by MALDI-TOF mass spectrometry. Nature communications. 5, 4763
4 Dzamko, N., et al. (2010) Inhibition of LRRK2 kinase activity leads to dephosphorylation of Ser(910)/Ser(935), disruption of 14-3-3 binding and altered cytoplasmic localization. Biochem J. 430, 405-413
5 Dzamko, N., et al. (2012) The IkappaB kinase family phosphorylates the Parkinson's disease kinase LRRK2 at Ser935 and Ser910 during Toll-like receptor signaling. PloS one. 7, e39132
6 Nichols, R. J., et al 2010) 14-3-3 binding to LRRK2 is disrupted by multiple Parkinson's disease-associated mutations and regulates cytoplasmic localization. Biochem J. 430, 393-404
7 Bouskila, M., et al (2011) TTBK2 kinase substrate specificity and the impact of spinocerebellar-ataxia-causing mutations on expression, activity, localization and development. Biochem J. 437, 157-167
8 Alessi, D. R., et al. (2014) The WNK-SPAK/OSR1 pathway: master regulator of cation-chloride cotransporters. Science signaling. 7, re3
9 Schumacher, F. R., et al (2014) Structural and biochemical characterization of the KLHL3-WNK kinase interaction important in blood pressure regulation. Biochem J. 460, 237-246
10 de Los Heros, P.,et al (2014) The WNK-regulated SPAK/OSR1 kinases directly phosphorylate and inhibit the K+-Cl- co-transporters. Biochem J. 458, 559-573
11 Ohta, A., et al (2013) The CUL3-KLHL3 E3 ligase complex mutated in Gordon's hypertension syndrome interacts with and ubiquitylates WNK isoforms: disease-causing mutations in KLHL3 and WNK4 disrupt interaction. Biochem J. 451, 111-122

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