Olli Silvennoinen - Publications#

Total publications 211, 23396 citations, H-index 70 (Google Scholar 25.1.2023)

10 career profiling publications:

O. Silvennoinen, J.N. Ihle, J. Schlessinger, D.E. Levy: Interferon-induced nuclear signaling by Jak protein tyrosine kinases. Nature, 1993, 366: 583-585.

A representative article of the postdoc period where Silvennoinen was centrally involved in the identification of the cytokine JAK-STAT signaling pathway.

P. Saharinen, K. Takaluoma, O. Silvennoinen: Regulation of the Jak2 tyrosine kinase by its pseudokinase domain. Mol. Cell. Biol., 2000, 20: 3387-3395.

J. Yang, S. Aittomäki, M. Pesu, K. Carter, J. Saarinen, N. Kalkkinen, E. Kieff, O. Silvennoinen: Identification of p100 as a coactivator for STAT6 that bridges STAT6 with RNA polymerase II. EMBO J., 2002, 21, 4950-4958.

The Silvennoinen laboratory has focused on molecular regulation of JAK kinases and STAT transcription factors. These two articles, the first describing the regulatory role of the pseudokinase domain in JAK activation, and the latter a multifunctional RNA binding protein p100/Tudor-SN/SND1 in transcriptional regulation directed the future studies of the laboratory. The concept of a dual regulatory function for the JAK pseudokinase domain, inhibition in the absence of cytokine but requirement for activation, has been confirmed in recent structural studies.

D. Ungureanu, J. Wu, T. Pekkala, Y. Niranjan, C. Young, O.N. Jensen, C-F Xu, T.A. Neubert, R.C. Skoda, S.R. 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.

The first molecular and functional characterization of the pseudokinase function in JAK kinases.

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.

The first crystal structures of JAK pseudokinase domain, both JAK2 WT and the predominant pathogenic mutation JAK2 V617F.

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.

Demonstration of the autoinhibitory interaction between the kinase and pseudokinase domains which provides also molecular explanation for most pathogenic JAK2 mutations .

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.

A.T. Virtanen, T. Haikarainen, P. Sampathkumar, M. Palmroth, S. Liukkonen, J. Liu, N. Nekhotiaeva, S.R. Hubbard, O. Silvennoinen. Identification of Novel Small Molecule Ligands for JAK2 Pseudokinase Domain. Pharmaceuticals, 2023, 16: :75. doi: 10.3390/ph16010075.

These studies demonstrate the critical function of ATP binding in JAK2 pseudokinase domain and provides the proof-of-concept that the ATP pocket is a relevant target for JAK inhibitors.

H.M. Hammarén, A.T. Virtanen, B.G. Abraham, H. Peussa, S.R. Hubbard, O. Silvennoinen: Janus kinase 2 activation mechanisms revealed by analysis of suppressing mutations. J Allergy Clin Immunol. 2019, 143, 1549-1559.

This study shows that JAK2 activation in cytokine receptors and in different pathogenic mutations are dependent on distinct regulatory domains and provide directions for mutant specific JAK2 inhibition.

M. Palmroth, K. Kuuliala, R. Peltomaa, A. Virtanen, A. Kuuliala, A. Kurttila, A. Kinnunen, M. Leirisalo-Repo, O. Silvennoinen, P. Isomäki. Tofacitinib Suppresses Several JAK-STAT Pathways in Rheumatoid Arthritis In Vivo and Baseline Signaling Profile Associates With Treatment Response. Front Immunol. 2021;12:738481. doi: 10.3389/fimmu.2021.738481.

Eight JAK inhibitors have been approved for inflammatory or hematological indications. These drugs are effective in relieving symptoms but only appr half of patients receive long-term remission. The paper describes the first clinical study to identify biomarkers that are predictive for JAK inhibitor responsiveness in patients.