About research group

We are investigating the molecular mechanisms of cytokine signalling with a goal to implement this information to dissect disease mechanisms and evaluate therapeutic strategies through proof-of-principle experiments in in vivo models and clinical material.

JAK-STAT pathway mediates important biological tasks ranging from blood formation to regulation of metabolism and orchestration of inflammatory and immune responses. Disturbances in cytokine signalling pathways lead to various human diseases, such as immune deficiencies, autoimmunity, allergy, metabolic diseases, myeloproliferative diseases and cancer. Understanding of the mechanisms of JAK/STAT activation at molecular and atomic level will provide the molecular basis for designing intervention strategies and methodology for screening and development of therapeutic compounds. The first JAK inhibitors are entering clinical use, but these drugs affect both normal and pathogenic JAKs thus show also adverse side-effects. We are now able to address some key questions in cytokine signalling and disease pathogenesis, specifically novel function of the pseudokinase domain in JAK kinases and the role of Tudor-SN protein in normal physiology and in disease models.

JAK kinases

Deregulated cytokine signalling is directly linked to cellular transformation and human cancer. Constitutive activation of JAKs and STATs is observed in several cancers including lymphoid and myeloid leukemias, multiple myeloma, in numerous human solid cancers of various origin. Myeloproliferative neoplasms (MPN) are clonal malignancies characterized by overproduction of one or more hematopoietic lineages. Mutations in the pseudokinase domains (JH2) of JAK2 were found to cause polycythemia vera (PV), essential thrombocythemia (ET), idiopathic myelofibrosis (IMF). Subsequently, JH2 domain has been found to be a hotspot for pathogenic and cancer causing mutations also in the other JAK kinases.

Understanding the function of JH2 domain is presently one of the most pressing questions in cytokine signaling. Our laboratory has conducted pioneering work in this area and demonstrated that JH2 negatively regulates the catalytic activity of JAK kinases, and this regulation is required to maintain JAK inactive in the absence of cytokine stimulation. Importantly, the mutation in MPN localizes in inhibitory region identified in our studies. However, the precise mechanism of JH2 function in JAK kinases and how the mutations cause aberrant signalling and diseases have been unknown.

We have recently demonstrated that JH2 in JAK2 is not a pseudokinase but a catalytically active, dual-specificity kinase. JH2 phosphorylates two negative regulatory residues (Ser523, Tyr570) and thereby control the basal JAK2 activity and cytokine signaling. Strikingly, MPN causing mutations abrogate JH2 catalytic activity and thereby relieve negative regulation (Ungureanu et al., Nature Struct Mol Biol, 2011). These findings change the concept of how JAK kinases and cytokine signaling is regulated and open a completely new direction of research.

Current studies focus on structural and functional aspects of JH2 in different JAK kinases using in vitro, cellular, in vivo models, and clinical samples, and evaluate the role of JH2 domain in human diseases.

Tudor-SN

The other major emphasis in our laboratory is to understand the mechanisms of transcriptional regulation. Through a direct proteome approach we have identified transcriptional coregulators for STAT6, and characterisation of these regulatory proteins in functional and structural terms is ongoing.  Our main interest is on Tudor-SN (p100), composed of repeats homologous to the Staphylococcal nucleases (SN) domain and a Tudor domain (TD). Our findings support a model, where Tudor-SN recruits acetyltransferase and helicase activity to the STAT6-driven promoter through interactions with CBP and RNA Helicase A and facilitate the access of STAT6-Tudor-SN complex to the basal transcriptional machinery. Transcriptional regulation is closely linked and coordinated with RNA processing events. We have shown that TD physically interacts with components of the spliceosome and facilitates pre-RNA splicing. The results suggest that Tudor-SN is a dual function regulator of gene expression that participates in both transcription and RNA metabolism via distinct domains. Tudor-SN is one of the most highly overexpressed genes in several cancers. We are currently evaluating the physiological function of Tudor-SN, and its role in various disease models.

The third research area relates to iPS (induced pluripotent stem) cell technology, where we are collaborating with Dr Aalto-Setälä´s group related to platform development and exploitation of the technology.

Major funding

Academy of Finland, Finnish Cancer Foundation,  Medical Research Fund of TaUH,  Sigrid Juselius Foundation,  Tampere Tuberculosis Foundation, Finnish Technology Agency TEKES.