To page body
university of tampere: faculty of medicine and life sciences: research: medical biochemistry:
Faculty of Medicine and Life SciencesUniversity of TampereFaculty of Medicine and Life Sciences

Molecular Immunology group

Cytokine signaling in Health and Disease

We investigate the molecular mechanisms of cytokine signaling by multidisciplinary approaches 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 functions ranging from blood formation to regulation of metabolism and orchestration of inflammatory and immune responses. Disturbances in cytokine signaling lead to various human diseases, such as immune deficiencies, autoimmunity, allergy, metabolic diseases, various leukemias and 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 for screening and development of therapeutic compounds. The first JAK inhibitors have entered clinical use and show beneficial clinical effects but these drugs are not optimal in terms of efficacy and selectivity for pathogenic signaling. Recent results in our laboratory have opened new insights into regulation of normal and pathogenic cytokine signaling and allow us to address some key questions in disease pathogenesis, specifically the function of the pseudokinase domain in JAK kinases and the role of SND1 protein in normal physiology and disease models.

JAK kinases

Deregulated cytokine signaling 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 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. However, the precise mechanism of JH2 function in JAK kinases and how the mutations cause aberrant signaling and diseases have been elusive.

We have demonstrated that JH2 in JAK2 and TYK2 are not bona fide pseudokinases but bind ATP. JAK2 JH2 harbours also catalytic activity and phosphorylates two negative regulatory residues (Ser523, Tyr570) to control the basal JAK2 activity. (Ungureanu et al., Nat Struct Mol Biol, 2011). We have determined the crystal structures of normal and pathogenic JAK2 and TYK2 JH2´s and the regulatory interaction between tyrosine kinase and pseudokinase domains in collaboration with Dr S. Hubbard and Dr Wang (Bandaranyake et al, Nat Struct Mol Biol, 2012, Shan et al., Nat Struct Mol Biol, 2014, Min et al., J Biol Chem, 2015). Recently we have demonstrated that the ATP-binding pocket of JAK2 JH2 regulates pathogenic JAK2 signaling and is a potential target for therapeutic interventions (Hammarén et al., Proc Natl Acad Sci, 2015). These findings change the concept of how JAKs and cytokine signaling are regulated and open new direction of research and therapeutic approaches. Current studies focus on structural and functional aspects on JAK kinases and other disease-associated pseudokinases.

SND1

The other major emphasis in our laboratory is to understand the mechanisms of transcriptional and epigenetic regulation. A proteome approach identified transcriptional coregulators for STAT6, and recently our main interest has been focused on SND1 (Tudor-SN). SND1 is composed of repeats homologous to the Staphylococcal nucleases (SN) domain and a Tudor domain (TD). Our findings support a model, where SND1 functions as a scaffold and recruits acetyltransferase and helicase activity to the STAT6-driven promoter through interactions with CBP and RNA Helicase A and facilitate the access of STAT6-SND1 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 SND1 is a dual function regulator of gene expression that participates in both transcription and RNA metabolism via distinct domains.

SND1 is one of the most highly overexpressed genes in several cancers including prostate, colon and breast cancer. We have established the first knockout model of SND1 that allows us to directly address the physiological function of SND1 and its role in various disease models.

The Group

Olli Silvennoinen

Bobin Abraham

Henrik Hammarén

Pia Isomäki (TAYS)

Saara Lehmusvaara

Krista Lehtinen

Merja Lehtinen

Maaria Palmroth

Juuli Raivola

Juha Saarikettu

Anniina Virtanen
0670.jpg

 

Major funding

Academy of Finland, Sigrid Juselius Foundation, Jane and Aatos Erkko Foundation, Finnish Cancer Foundation,  Medical Research Fund of TaUH,  Tampere Tuberculosis Foundation.

Recent publications

H. Hammarén, D. Ungureanu, J. Grisouard, R.C. Skoda, S.R. Hubbard, O. Silvennoinen: ATP binding to the JAK2 pseudokinase domain is critical for pathogenic activation. Proc. Natl. Acad. Sci., 2015, 112, 4642-4647.

O. Silvennoinen, S.R. Hubbard: Molecular insights into regulation of JAK2 in myeloproliferative neoplasms. Blood, 2015, 125, 3388-3392.

O. Silvennoinen, S.R. Hubbard: Targeting the inactive conformation of JAK2 in hematological malignancies. Cancer Cell, 2015, 28, 1-2.

X. Min, D. Ungureanu, S. Maxwell, H. Hammaren, S. Thibault, J. Eksterowicz, E.-K. Hillert, M. Ayres, B. Greenfield, C. Gabel, N. Walker, O. Silvennoinen*, Z. Wang*: Structural and functional characterization of TYK2 JH2 domain reveals a regulatory mechanism for catalytic function in pseudokinases. J. Biol. Chem. 2015, 290, 27261-27270.

P. Isomäki, I. Junttila, K. Vidqvist, M. Korpela and O. Silvennoinen Constitutive activation of STAT3 in rheumatoid arthritis correlates with IL-6 levels.  Rheumatol., 2015, 54, 1103-1113.

M. Pertovaara, O. Silvennoinen, P. Isomäki: STAT5 is constitutively activated in T cells, B cells and monocytes from patients with primary Sjögren´s syndrome. Clin Exp Immunol., 2015, 181, 29-38.

C. Su, C. Zhang, A. Tecle, X. Fu, J. He, J. Song, W. Zhang, X. Sun, Y. Ren, O. Silvennoinen, Z. Yao, X. Yang, M. Wei, J. Yang: Tudor Staphylococcal Nuclease (Tudor-SN), a Novel Regulator Facilitating G1/S Phase Transition, Acting As a Co-activator of E2F-1 in Cell Cycle Regulation. J. Biol. Chem., 2015, 290, 7208-7220.

X. Gao, X. Fu, J.Song,Y. Zhang, X. Cui, C. Su, L.Ge, J. Shao, L.Xin, J.Saarikettu, M. Mei, X. Yang, M. Wei, O. Silvennoinen, Z. Yao, J. He, J. Yang: Poly(A)+ mRNA-binding protein Tudor-SN regulates stress granules aggregation dynamics. FEBS J., 2015, 282, 874-890

Y. Shan, K. Gnanasambandan, D. Ungureanu, E.T. Kim, K. Yamashita, O. Silvennoinen, D.E. Shaw, S.R. Hubbard: Molecular basis for pseudokinase-dependent autoinhibition and oncogenic activation of JAK2 tyrosine kinase. Nat. Struct. Mol. Biol., 2014, 21, 579-584.

A. Sanz Sanz#, Y. Niranjan#, H. Hammarén, D. Ungureanu, R. Ruijtenbeek, I.P. Touw, O. Silvennoinen*, R. Hilhorst*: The JH2 domain and SH2-JH2 linker regulate JAK2 activity: a detailed kinetic analysis of wild type and V617F mutant kinase domains. Biochim. Biophys. Acta, 2014, 1844, 1835-1841.

L.M. Varghese, D. Ungureanu, N.P. Liau, S.N. Young, A. Laktyushin, H. Hammarén, I.S. Lucet, N.A. Nicola, O. Silvennoinen, J.J. Babon, J.M. Murphy: Mechanistic insights into activation and SOCS3-mediated inhibition of myeloproliferative neoplasm-associated JAK2 mutants from biochemical and structural analyses. Biochem. J. 2014, 458, 395-405.

J.M.  Murphy , Q. Zhang , S.N. Young , M.L. Reese , F.P. Bailey , P. A. Eyers , D. Ungureanu , H. Hammarén, O. Silvennoinen , L.N. Varghese , K. Chen , A. Tripaydonis , N. Jura , K. Fukuda , J. Qin , Z. Nimchuk ,  M.B. Mudgett , S. Elowe , C.L. Gee , L. Liu , R.J. Daly , G. Manning , J.J. Babon , I.S. Lucet . A robust methodology to subclassify pseudokinases based on their nucleotide binding properties. Biochem. J. 2014, 457, 323-334.

M.Cappellari, P. Bielli, M. P. Paronetto, F. Ciccosanti, G. M. Fimia, J. Saarikettu, O. Silvennoinen, C. Sette: The transcriptional coactivator SND1 is a novel regulator of alternative splicing in prostate cancer cells. Oncogene, 2014, 33, 3794-3802.

Z. Duan ,X.  Zhao , X. Fu , C. Su , L.  Xin , J. Saarikettu , X. Yang , Z. Yao , O. Silvennoinen , M. Wei , J. Yang : Tudor-SN, a Novel Coactivator of Peroxisome Proliferator-activated Receptor γ Protein, Is Essential for AdipogenesisJ. Biol Chem. 2014, 289. 8364-74.

X. Gao, X. Shi, X. Fu, L. Ge, Y. Zhang, C. Su, X. Yang, O. Silvennoinen, Z. Yao, J. He, M. Wei, J. Yang: Human Tudor Staphylococcal Nuclease (Tudor-SN) protein modulates the kinetics of AGTR1-3'UTR granule formation. FEBS Lett., 2014, 588, 2154-2161.

Y. Niranjan, D. Ungureanu, H. Hammarén, A. Sanz-Sanz2, A. H. Westphal, J. W. Borst, O. Silvennoinen, R. Hilhorst: Analysis of steady-state Förster resonance energy transfer data by avoiding pitfalls: Interaction of JAK2 tyrosine kinase with N-methylanthraniloyl -nucleotides Anal. Biochem., 2013, 442:213-222.

O. Silvennoinen, D. Ungureanu, Y. Niranjan, H. Hammaren, R. Bandaranayake, S.R. HubbardNew insights into the structure and function of the pseudokinase domain in JAK2. Biochem. Soc. Trans., 2013;41(4):1002-7.

R.M. Bandaranayake*, D. Ungureanu*, Y. Shan, D.E. Shaw, O. Silvennoinen*, S.R. Hubbard*: Crystal structures of the Jak2 pseudokinase domain and the pathogenic mutant V617F. (* equal contribution, correspondence). Nat. Struct. Mol. Biol., 2012, 19, 754-760. 

A. Laurence, M. Pesu, O. Silvennoinen, J. O’Shea: JAK Kinases in Health and Disease: An Update. Open Rheum. J., 2012, 6, 232-244.

T. Fashe, J. Saarikettu, P. Isomäki, J. Yang, O. Silvennoinen: Expression analysis of Tudor-SN protein in mouse tissues, Tissue Cell, 2013, 45, 21-31.

X. Gao, X. Zhao, Y. Zhu, J. He, J. Shao, C. Su, Y. Zhang, W. Zhang, J. Saarikettu, O. Silvennoinen, Z. Yao, J. Yang. Tudor Staphylococcal Nuclease (Tudor-SN) participates in small ribonucleoprotein (snRNP) assembly via interacting with symmetrically dimethylated Sm proteins. J. Biol. Chem. 2012, 287, 18130-18141.

J. Grönholm, M. Kaustio, H. Myllymäki, J. Kallio, J. Saarikettu, J. Kronhamm, S. Valanne, O.Silvennoinen, M. Rämet: Not4 enhances JAK/STAT pathway dependent gene expression in Drosophila and in human cells. FASEB J., 2012, 26, 1239-1250.

A.L. Lahti, V.J. Kujala, M. Pekkanen-Mattila, E. Kerkelä, H. Chapman, A.-P. Koivisto, J. Hyttinen, K. Kontula, H. Swan, B. Conklin, S. Yamanaka, O. Silvennoinen and K. Aalto-Setälä: Model for long QT syndrome type 2 using human iPS cells demonstrates arryhtmogenic characterictics in cell culture. Dis Model Mech. 2012, 5, 220-230.

K. Kujala, J. Paavola, A. Lahti, K. Larsson, M. Pekkanen-Mattila, M. Viitasalo, A. Lahtinen, L. Toivonen, K. Kontula, H. Swan, M. Laine, O. Silvennoinen, K. Aalto-Setälä: Cell Model of Catecholaminergic Polymorphic Ventricular Tachycardia Reveals Early and Delayed Afterdepolarizations.  Plos One, 2012, 2012;7:e44660.

D. Ungureanu, J. Wu, T. Pekkala, Y. Niranjan, C. Young, O.N. Jensen, C-F Xu, T.A. Neubert, S. Hubbard, O. Silvennoinen: The pseudokinase domain of JAK is a dual-specificity protein kinase that negatively regulates cytokine signaling. Nat. Struct. Mol. Biol., 2011, 18:971-976.

 
Maintained by: med.info@uta.fi
Last update: 25.8.2016 10.57 Muokkaa

University of Tampere
+358 3 355 111
registry@uta.fi


FINEEC Audited HR Excellence in Research

THE UNIVERSITY
Research
Admissions
Studies
News
Cooperation and Services
About Us

CURRENT ISSUES
Research & Study
Tampere3
Vacancies

SERVICES
Administration
Career Services
Finnish Social Science Data Archive
Centre for International Education
IT services
Language Centre
Language Services
Library
Registrar's Office
Registry
Sports Activities
» more

STUDIES
Teaching schedules
Curricula guides
Student's Desktop

ONLINE SERVICES
Andor search
Renew your loans
UTA intranet
Office 365 webmail
Uta webmail
Moodle
NettiOpsu
NettiKatti
TamPub
Electronic exam service
Examination results