Intramolecular regulation of Janus kinases

Event start date
Event start time
12.00
Place

Arvo building, Jarmo Visakorpi auditorium, address: Arvo Ylpön katu 34.

Henrik Hammarén

Doctoral defence of M.Sc. Henrik Hammarén

Intramolecular regulation of Janus kinases

The field of science of the dissertation is Medical Biochemistry .

The opponent is professor Stefan Knapp (Goethe University Frankfurt, Germany). Professor Olli Silvennoinen acts as the custos.

The language of the dissertation defence is English.

Understanding the functions of the signalling protein JAK2 controlling blood cell formation in health and disease

The human body produces around 100 billion to 1 trillion new blood cells daily in a process called haematopoiesis. This process is controlled by a network of signalling proteins called cytokines. Cytokines signal by binding to special proteins called cytokine receptors on the surfaces of cells and cause the cell to change its functions. The relaying of signals from cytokines to the inside of the cell is called signal transduction. Signal transduction by cytokine receptors is mediated inside the cell by a group of signalling proteins called Janus kinases or JAKs. Correct function of JAKs is critical for the function of cytokines and haematopoiesis, as is seen in diseases, in which JAKs do not function properly due to mutations in the genes coding for JAKs. These mutations can cause JAKs to signal too much leading, for example, to overproduction of red blood cells in a disease called polycythemia vera or PV, or to overproduction of white blood cells (leukemia). Mutations causing these diseases usually arise spontaneously in the stem cells producing blood cells, and thus only a part of the stem cells carry mutated JAKs. Cytokine signalling through JAKs also controls many other biological processes, such as growth, metabolism, and control of the immune system.

We studied the functions of JAKs with a focus on a substructure of JAKs, called the pseudokinase domain (or JH2) which is important in the regulation of JAK functions. We characterized the pseudokinase domain of JAK2, which is the particular JAK mutated in PV. We used laboratory cell culture models, targeted introduction of mutations, as well as computer-assisted molecular modelling. We discovered that targeted alteration of a certain JH2 substructure could suppress JAK2 signalling caused by disease mutations, while leaving normal JAK2 signalling unaffected. These results were further verified in a PV mouse model by our collaborators. Our results indicate that JH2 could be a good target for new drugs, which could affect only the cells carrying mutated forms of JAK2, thus leaving the normal production of blood cells intact. These drugs could be a distinct improvement over current drugs used to treat PV, as current drugs affect both healthy and mutated cells.

In a collaboration effort with researchers from New York (USA), we also generated a molecular model for the functions of JH2 in regulating signalling of JAKs. This model explains the mechanism, how most known JAK mutations act on the molecule to cause too much signalling. We further studied the functions of JH2 in the signalling of various cytokines, and found functional differences, which could in the future be potentially used to make more specific drugs against JAKs.

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The dissertation is published in the publication series of Acta Universitatis Tamperensis; 2338, Tampere University Press, Tampere 2017. The dissertation is also published in the e-series Acta Electronica Universitatis Tamperensis; 1843, Tampere University Press 2017.

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