Suomeksi
 
 
Intracellular signalling regulated by Pim kinases
 Ongoing projects:
  • Pim substrates in regulation of metastatic growth of prostate cancer cells (project funded by the Academy of Finland)
  • Development and validation of novel inhibitors for Pim kinases
  • C. elegans nematodes as a model system to study evolutionarily conserved physiological phenomena regulated by Pim-related kinases
  • Nematodes as biosensors for indoor air problems (project funded by the Finnish Work Environment Fund) or other environmental factors

Description of the projects​

The studies of our research group focus on the signalling pathways regulated by the Pim family of serine/threonine-specific protein kinases. We have shown that the three highly homologous members of this family are expressed in partially overlapping patterns, mainly in cells of the immune or the nervous system, but also in epithelia. In hematopoietic cells, pim expression can be induced by multiple cytokines and also by some hormones, suggesting a role for Pim kinases in signal transduction initiated by cytokine or hormone receptors. When overexpressed in lymphoid tissues of transgenic mice, pim genes promote lymphomagenesis, especially in cooperation with other oncogenic genes that either enhance cell proliferation (myc) or cell survival (bcl-2). We and others have observed that in human cancer patients, elevated levels of pim-1 mRNA and protein can be found in hematological malignancies like lymphomas and in solid cancers like prostate cancer. Moreover, we have shown that pim-1 overexpression confers radioresistance to cells derived from squamous cell carcinomas.

We have previously shown that Pim kinases stimulate activities of several cellular or viral transcription factors such as Myb, NFATc, EBNA2, LANA as well as RUNX family members. We have set up the fluorescence resonance energy transfer (FRET), fluorescence recovery after photobleaching (FRAP) and fluorescence-lifetime imaging microscopy (FLIM) techniques to be able to visualize intracellular trafficking and interactions between Pim-1 and its substrates. We have also analysed expression of pim family genes during cytokine-dependent T helper cell differentiation and shown that in hematopoietic cells, Pim kinases promote cytokine-independent survival and inhibit apoptosis by several mechanisms, including upregulated expression of the anti-apoptotic Bcl-2 protein and phosphorylation-induced inactivation of the pro-apoptotic Bad protein. Altogether, our studies based on domestic or international collaborations have had a major impact to the understanding of Pim kinase activities in both normal and transformed cells. 

To further characterize the signalling pathways downstream of Pim kinases, we have used phosphoproteomics and other approaches to identify novel substrates for Pim kinases. Several proteins have been confirmed as true Pim substrates and their functional validation is underway using overexpression, RNA interference as well as CRISPR/Cas9-based gene editing. We have also been involved in developing sensitivity of the methodology to recognize phosphorylation target sites within Pim substrates. In addition, we have been collaborating with several groups of chemists to identify and validate Pim-specific small molecule inhibitors, which have provided great tools for our research, but may also have therapeutic value. Using these inhibitors, we have revealed a novel role for Pim kinases in stimulation of cancer cell migration and invasion and shown that one of our Pim-selective inhibitors can efficiently block metastasis of cancer cells from the prostate to other organs such as the lungs. We have also been to identify several Pim substrates as mediators of its pro-migratory effects. These include the transcription factors NFATc1 and FoxP3, the GSK3B kinase as well as the chemokine receptor CXCR4, whose activities are either stimulated or inhibited by Pim-dependent phosphorylation. In addition, we have shown that Pim kinases and their most novel substrate Notch1 synergistically enhance tumorigenic growth of breast and prostate cancer cells. 

Recently we have been able to show that our Pim inhibitors also block the activity of the Pim-related kinases of the nematode C. elegans, which has allowed us to initiate interesting studies on evolutionary conserved signalling pathways with physiological relevance. Therefore, we have set up a facility to culture nematodes for both teaching and research purposes. Furthermore, we have acquired nematode strains carrying stress-responsive fluorescent reporters and are currently testing whether they can be utilized to biomonitor sublethal effects of environmental factors such as heavy metals or indoor air toxins. 

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Group Members

  • Päivi Koskinen, PhD,       Adj. professor,           principal investigator
  • Eeva Rainio, PhD, co-supervisor
  • Sari Paavanen-Huhtala, PhD, senior researcher
  • Niina Santio, PhD, postdoctoral fellow
  • Ralica Arnaudova, MSc
  • Sini Eerola, MSc
  • Alan Mung, MSc
  • Riitta Vahakoski, MSc
  • Jani Ylä-Pelto, MSc
  • William Eccleshall, BSc
  • Joel Tuomaala, BSc
  • Veera Vainio, BSc

Contact information​

paivi.koskinen (at) utu.fi

Recent publications

Kiriazis A, Aumüller IB, Arnaudova R, Brito V, Rüffer T, Lang H, Silvestre SM, Koskinen PJ, Yli-Kauhaluoma J. Nucleophilic substitution of hydrogen facilitated by quinone methide moieties in benzo[cd]azulen-3-ones. Org Lett, 19, 2030-2033, 2017. PMID: 28379712​ 

Santio NM, Landor SKJ, Vahtera L, Ylä-Pelto J, Paloniemi E, Imanishi SY, Gorthals G, Varjosalo M, Manoharan G, Uri A, Lendahl U, Sahlgren C & Koskinen PJ. Phosphorylation of Notch1 by Pim kinases promotes oncogenic signaling in breast and prostate cancer cells. Oncotarget, 7, 43220-43238, 2016. PMID: 27281612

Santio NM, Salmela M, Arola H, Eerola SK, Heino J, Rainio EM, Koskinen PJ. The PIM1 kinase promotes prostate cancer cell migration and adhesion via multiple signalling pathways. Exp Cell Res, 342, 113-124, 2016. PIMID: 26934497 

Santio NM, Eerola SK, Paatero I, Yli-Kauhaluoma J, Anizon F, Moreau P, Tuomela J, Härkönen P, Koskinen PJ. Pim kinases promote migration and metastatic growth of prostate cancer xenografts. PLoS ONE 10, e0130340, 2015. PMID: 26075720​

Kiriazis A, Vahakoski RL, Santio NM, Arnaudova R, Eerola SK, Rainio EM, Aumüller IB, Yli-Kauhaluoma J, Koskinen PJ. Tricyclic benzo[cd]azulenes selectively inhibit activities of Pim kinases and restrict growth of Epstein-Barr virus-transformed cells. PLoS ONE 8, e55409, 2013. PMID: 23405147

​Tahvanainen J, Kyläniemi MK, Kanduri K, Gupta B, Lähteenmäki H, Kallonen T, Rajavuori A, Rasool O, Koskinen PJ, Rao KV, Lähdesmäki H, Lahesmaa R. Proviral integration site for Moloney murine leukemia virus (PIM) kinases promote T helper 1 cell differentiation. J. Biol. Chem. 288,3048-3058, 2013. PMID: 23209281

Sarek G, Ma L, Enbäck J, Järviluoma A, Moreau P, Haas J, Gessain A, Koskinen PJ, Laakkonen P & Ojala PM. Kaposi´s sarcoma herpesvirus lytic replication compromises apoptotic response to p53 reactivation in virus-induced lymphomas. Oncogene 32, 1091-1098, 2013. PMID: 22469985

Letribot B, Akué-Gédu R, Santio NM, El-Ghozzi M, Avignant D, Cisnetti F, Koskinen PJ, Gautier A, Anizon F & Moreau P. Use of copper(I) catalyzed azide alkyne cycloaddition (CuAAC) for the preparation of conjugated pyrrolo[2,3-a]carbazole Pim kinase inhibitors. Eur. J. Med. Chem. 50, 304-310, 2012. PMID: 22386260

Kouvonen P, Rainio EM, Suni V, Koskinen P & Corthals G. Enrichment and sequencing of phosphopeptides using indium tin oxide coated glass slides. Mol. BioSyst. 7, 1828-1837, 2011. PMID: 21523302

Santio NM, Vahakoski RL, Rainio EM, Sandholm JA, Virtanen SS, Prudhomme M, Anizon F, Moreau P & Koskinen PJ. Pim-selective inhibitor DHPCC-9 reveals Pim kinases as potent stimulators of cancer cell migration and invasion. Mol. Cancer 9, 279, 2010. PMID: 20958956

Kouvonen P, Rainio EM, Suni V, Koskinen P & Corthals G. Data combination from multiple matrix-assisted laser desorption/ionization (MALDI) matrices: opportunities and limitations for MALDI analysis. Rapid Commun. Mass Spectrom. 24, 1-3, 2010. PMID: 21072807

Peltola KJ, Hollmén M, Maula SM, Rainio EM, Ristamäki R, Luukkaa M, Sandholm J, Sundvall M, Elenius K, Koskinen PJ, Grenman R & Jalkanen S. Pim-1 kinase expression predicts radiation response in squamocellular carcinoma of head and neck and is under the control of epidermal growth factor receptor. Neoplasia 11, 629-636, 2009. PMID: 19568408

Cheng F, Weidner-Glunde M, Varjosalo M, Rainio EM, Lehtonen A, Schulz TF, Koskinen PJ, Taipale J & Ojala PM. KSHV reactivation from latency requires Pim-1 and Pim-3 kinases to inactivate the latency-associated nuclear antigen LANA. PLoS Pathogens, 5, e1000324, 2009. 19266083​