University of Dundee

Professor Dario Alessi FRS FRSE

Understanding signalling pathways mutated in inherited disorders
Position: 
Professor of Signal Transduction and Director of MRC Protein Phosphorylation and Ubiquitylation Unit (MRC-PPU) and the Division of Signal Transduction Therapy Unit (DSTT)
Address: 
School of Life Sciences, University of Dundee, Dundee
Full Telephone: 
+44 (0) 1382 385602, int ext 85602
Email: 

Biography

Dario received his BSc in Biochemistry from the University of Birmingham in 1988 and obtained a Ph.D. in 1991 for his work on the synthesis and use of spin-labelled ATP analogues to study muscle contraction under the joint supervision of Ian Trayer (University of Birmingham) and David Trentham FRS (National Institute of Medical Research, Mill Hill, London).  He then carried out postdoctoral research with Philip Cohen in the MRC PPU from 1991 to 1997, where he became fascinated by protein kinases and how they control almost all aspects of cell biology.

In 1998 Dario became a Programme Leader in the MRC PPU, and assumed the Directorship of the Unit in April 2012.  Dario has received many awards and honours, including the Colworth Medal in 1999 (Biochemical Society), membership of EMBO (2005), the EMBO Gold Medal (2005), and fellowship of the Royal Society of Edinburgh (2002), the Royal Society of London (2008), and the Medical Academy of Science (2012).

Research

Protein phosphorylation and ubiquitylation pathways play a central role in human diseases such as Parkinson’s, cancer and hypertension. Mutations in protein kinases cause around 1% of all Parkinson’s disease, and many kinases and ubiquitylation enzymes are mutated in human cancer and hypertension.

Our group focuses on understanding the components of signalling pathways that are mutated in neurodegenerative movement disorders (LRRK2, Fbxo7, PINK1, Parkin, TTBK2), hyperstension (WNK1, WNK4, SPAK, OSR1, Cullin3 and KLHL3) and cancer (PDK1, Akt, SGK, mTOR, LKB1, ARK5/NUAK1 and AMPK). The aim of our research is to work out how these pathways are organised, how they recognise signals, how the signal moves down the pathway to elicit physiological responses and what goes wrong in human disease. We hope that our findings will enable researchers to play the engineer in devising new strategies to treat disease.

In collaboration with Matthias Mann, we recently identified the first physiological substrate for the Parkinson’s disease-associated LRRK2 protein kinase, by showing that LRRK2 directly phosphorylates a subset of the Rab GTPases, on a residue lying within the middle of the effector interacting-switch II domain. We also defined a novel pathway by which the SGK3 protein kinase is activated, and found that SGK3 isoforms contribute to the resistance of breast cancer cells to Akt and PI3-kinase inhibitors. In collaboration with Thimo Kurz, we demonstrated that the KLHL3:CUL2 ubiquitin E3 ligase complex is mutated in patients with Gordon’s hypertension syndrome.

Publications

Selected Recent Publications

  1. Steger, M., Tonelli, F., Ito, G., Davies, P., Trost, M., Vetter, M., Wachter, S., Lorentzen, E., Duddy, G., Wilson, S., Baptista, M.A.S., Fiske, B.K., Fell, M.J., Morrow, J.A., Reith, A.D., Alessi, D. R. and Mann, M. (2016) Phosphoproteomics reveals that Parkinson’s disease kinase LRRK2 regulates a subset of Rab GTPases. eLife DOI: http://dx.doi.org/10.7554/eLife.12813 [Dario Alessi and Matthias Mann Joint corresponding authors]
  2.  Zhang, N., Gordon, S.L., Fritsch, M.J., Esoof, N., Campbell, D.G., Gourlay, R., Velupillai, S., Macartney, T., Peggie, M., van Aalten, D.M.F., Cousin, M.A.  Dario R. Alessi and Alessi, D. R. (2015) Phosphorylation of SV2A at Thr84 by CK1 family kinases controls the specific retrieval of synaptotagmin-1. Journal of Neuroscience 35, 2492-250.
  3. Zhang, J, Siew, K, Macartney, T, O'Shaughnessy, K,M, Alessi, D. R. (2015) Critical role of the SPAK protein kinase CCT domain in controlling blood pressure. Hum Mol Genet. 24, 4545-4558
  4. Perez-Oliva, A.B., Lachaud, C., Szyniarowski, P., Muñoz, I., Macartney, T., Hickson, I., Rouse, R., and Alessi, D. R. (2015) USP45 deubiquitylase controls ERCC1-XPF endonuclease mediated DNA damage responses. EMBO J. 34, 326-343.
  5.  Bago, R., Malik, N., Munson, M.J., Prescott, A.R., Davies, P., Sommer, E., Shpiro, N., Ward, R., Cross, D., Ganley, I.G and Alessi, D. R. (2014) Characterisation 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 PI-3 kinase. Biochemical J 463, 413-427.
  6.  Alessi, D. R., Zhang, J., Khanna, A., Hochdörfer, T., Shang, Y., and Kahle, K.T. (2014) The WNK-SPAK/OSR1 pathway: Master regulator of cation-chloride cotransporters. Science signalling 7, Re3
  7. Banerjee S., Zagorska A., Deak M., Campbell D.G., Prescott A., and Alessi, D. R. (2014) Interplay between Polo kinase, LKB1-activated NUAK1 kinase, PP1βMYPT1 phosphatase complex and the SCFβTrCP E3 ubiquitin ligase. Biochemical J 461, 233-245.
  8.  van der Wijst, J., Blanchard, M.G., Woodroof, H.I., Macartney, T.J., Gourlay, R., Hoenderop, J.G., Bindels, R.J., and Alessi, D. R. (2014) Kinase and channel activity of TRPM6 are coordinated by a dimerization motif and pocket interaction. Biochemical Journal. 460,165-175.
  9.  Houde, V,P., Ritorto, M,S., Gourlay,. R, Varghese, J., Davies, P., Shpiro, N., Sakamoto, K. and Alessi, D. R. (2014) Investigation of role that LKB1 Ser431 phosphorylation and Cys433 farnesylation play by mouse knock-in analysis reveals an unexpected role of prenylation in regulating AMPK activity. Biochemical Journal 458, 41-56.
  10. Sommer, E.M., Dry, H., Cross, D., Guichard, S., Davies, B.R. and Alessi, D. R. (2013) Elevated SGK1 predicts resistance of breast cancer cells to Akt inhibitors. Biochemical Journal 452, 499-508.

Impact

Commercial Impact:

In collaboration with the pharmaceutical industry via the Division of Signal Transduction Therapy collaboration with AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Janssen Pharmaceutica, Merck Serono and Pfizer the research ouptuts from my group contribute to accelerating the development of company drug development programmes through access to research data and reagents. Reagents are also commercialised to provide access to the wider scientific community via license arrangements with companies such as Millipore, AbCam and Ubiquigent.