Tumour Suppressor Signalling Networks
Group Leader: Dr Alexander Hergovich
In cancer development the coordination of cell death and multiplication is misbalanced, which combined with genetic instability, can result in aggressive tumour growth. We are interested in understanding mammalian Hippo tumour suppressor signalling that appears to function in all these three cancer driving processes.
Tumour cells need to acquire several key features that allow their long-term survival. Cancer cells combine increased cell proliferation with decreased cell death rates in order to achieve efficient tumour growth. Another major feature of tumour cells is increased genetic instability, where recent evidence suggests that centrosome abnormalities can induce tumours by increasing genetic instability.
Significantly, in mammals the MST/hMOB/LATS/NDR tumour suppressor cascades (also termed mammalian Hippo signalling) coordinate cell death and proliferation, and function in the regulation of centrosome duplication. Altogether, NDR/LATS kinase signalling is part of the molecular control of several cancer-related processes.
In spite of recent progress made in our understanding of mammalian Hippo signalling, the complexity of this pathway is far from being understood (mammalian cells encode 5 different MST kinases, 6 different MOB co-activators, 2 NDR, and 2 LATS kinases). Therefore, my laboratory addresses how centrosome biology, cell cycle progression, cell proliferation and apoptosis are controlled by this complex machinery. We use various techniques and mutant variants of MST/hMOB1/NDR/LATS proteins, in order to dissect the biological importance of protein-protein interactions and kinase activities.
The main aim is to decipher and understand the key steps that are essential for the anti-cancer activities of these tumour suppressor proteins. Overall, the precise characterisation of these tumour suppressor networks might open novel avenues in the fight against human cancer. On the long-term, understanding where, how and why these tumour suppressor proteins are required for tumour suppression might also help to establish how far these proteins can be used as read-outs in the detection, prognosis and treatment of cancer.
Hergovich, A., and Hemmings, B.A. Hippo signalling in the G2/M cell cycle phase: Lessons learned from the yeast MEN and SIN pathways. Seminars in Cell & Developmental Biology 23(7), 794-802 (2012).
Hergovich, A. Mammalian Hippo signalling: a kinase network regulated by protein-protein interactions. Biochemical Society Transactions 40(1), 124-128 (2012).
Zhou, Y., Adolfs, Y., Pijnappel, W.W., Fuller, S.J., Van der Schors, R.C., Li, L.W., Sugden, P.H., Smit, A.B., Hergovich, A., and Pasterkamp, R.J. MICAL-1 is a negative regulator of MST-NDR kinase signaling and apoptosis. Molecular and Cellular Biology 31(17): 3603-3015 (2011).
Hergovich, A. MOB control: Reviewing a conserved family of kinase regulators. Cellular Signalling 23: 1433-1440 (2011).
Cornils, H., Kohler, R.S., Hergovich, A., and Hemmings, B.A. Human NDR kinases control G1/S cell cycle transition by regulating p21 and c-myc stability. Molecular and Cellular Biology 31(7): 1382-1395 (2011).
Kohler, R.S., Schmitz, D., Cornils, H., Hemmings, B.A., and Hergovich, A. Characterization of the family of human MOB proteins reveals hMOB2 as a inhibitory regulator of human NDR kinases. Molecular and Cellular Biology 30(18), 4507-4520 (2010).
Cornils, H., Stegert, M.R., Hergovich, A., Hynx, D., Schmitz, D., Dirnhofer, S., and Hemmings, B.A. Ablation of mammlian NDR1 kinase predisposes mice to T-cell lymphoma development. Science Signaling (126), ra47 (2010).
Hergovich, A., and Hemmings, B.A. TAZ-mediated crosstalk between Wnt and Hippo signaling. Developmental Cell 18(4), 508-509 (2010).
Hergovich, A., Kohler, R.S., Schmitz, D., Vichalkovski, A., Cornils, H., and Hemmings, B.A. The MST1 and hMOB1 tumor suppressors control human centrosome duplication by regulating NDR kinase phosphorylation. Current Biology 19(20):1692-1702 (2009).
Hergovich, A., Lamla, S., Nigg, E.A., and Hemmings, B.A. Centrosome-associated NDR kinase regulates centrosome duplication. Molecular Cell 25(4), 625-634 (2007).
Hergovich, A., Stegert, M.R., Schmitz, D., and Hemmings, B.A. NDR kinases regulate essential cell processes from yeast to humans. Nature Reviews Molecular Cell Biology 7(4), 253-264 (2006).
Hergovich, A., Bichsel, S.J., and Hemmings, B.A. Human NDR kinases are rapidly activated by MOB proteins through recruitment to the plasma membrane and phosphorylation. Molecular and Cellular Biology 25(18), 8259-8272 (2005).