Dario Alessi's Research Group

Pubmed | Biography


Signalling pathways in inherited disorders

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.

Alessi Lab Group Photo

People

Adil Sarhan Almuntafeky | Postdoctoral Researcher
Ruzica Bago | Postdoctoral Researcher
Kristin Balk | PhD Student
Sophie Burel | Postdoctoral Researcher
Gerrit Daubner | Postdoctoral Researcher
Federico Diez | Postdoctoral Researcher
Ying (Ivonna) Fan | Postdoctoral Researcher
Athanasios Karapetsas | Postdoctoral Researcher
Pawel Lis | Postdoctoral Researcher
Nazma Malik | PhD Student
Chiara Maniaci | Visiting Student
Rafeeq Mir | Postdoctoral Researcher
Raja Sekhar Nirujogi | Postdoctoral Researcher
Elena Purlyte | PhD Student
Esther Sammler | Postdoctoral Researcher
Anna Tasegian | Postdoctoral Researcher
Francesca Tonelli | Postdoctoral Researcher
Hannah Tovell | PhD Student
Jinwei Zhang | Postdoctoral Researcher

Selected Publications

Bago, R., Sommer, E., Castel, P., Crafter, C., Bailey, F.P., Shpiro, N., Baselga, J., Cross, D., Eyers, P.A. and Alessi, D. R. (2016) The hVps34-SGK3 pathway alleviates sustained PI3K/Akt inhibition by stimulating mTORC1 and tumour growth. EMBO J 35 1902-1922
Ito, G., Katsemonova, K., Tonelli, F., Lis, P., Baptista, M., Shpiro, N., Duddy, G., Wilson, S., Ho, W.L., Ho, S.L., Reith, A.D. and Alessi, D. R. (2016) Phos-tag analysis of Rab10 phosphorylation by LRRK2: a powerful assay for assessing kinase function and inhibitors Biochem J. 473 2671-2685
Steger, M., Tonelli, F., Ito, G., Davies, P., Trost, M., Vetter, M., Wachter, S., Lorentzen, E., Duddy, G., Wilson, S., Baptista, M. A., Fiske, B. K., Fell, M. J., Morrow, J. A., Reith, A. D., Alessi, D. R., Mann, M. (2016) Phosphoproteomics reveals that Parkinson's disease kinase LRRK2 regulates a subset of Rab GTPases Elife 5 e12813
Schumacher, F. R., Sorrell, F. J., Alessi, D. R., Bullock, A. N., Kurz, T. (2014) Structural and biochemical characterization of the KLHL3-WNK kinase interaction important in blood pressure regulation Biochem J 460 237-246
Bago, R., Malik, N., Munson, M. J., Prescott, A. R., Davies, P., Sommer, E., Shpiro, N., Ward, R., Cross, D., Ganley, I. G., Alessi, D. R. (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
Ritorto, M. S., Ewan, R., Perez-Oliva, A. B., Knebel, A., Buhrlage, S. J., Wightman, M., Kelly, S. M., Wood, N. T., Virdee, S., Gray, N. S., Morrice, N. A., Alessi, D. R., Trost, M. (2014) Screening of DUB activity and specificity by MALDI-TOF mass spectrometry Nat Commun 5 4763