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Dr Jan Jongstra, Ph.D.

Dr Jan Jongstra, Ph.D.

Position:

  • Senior Scientist, Genetics and Development, University Health Network, Toronto Western Research Institute

Credentials:

  • Assiciate Professor, Department of Immunology at University of Toronto

Biography:

The role of PIM kinases in the regulation of major proliferative signaling pathways.

            The PIM family of oncogenic serine/threonine kinases consists of three members, PIM-1, PIM-2 and PIM-3 and are involved in formation of lymphoid and solid tumours.  PIM-1 and PIM-2 are implicated in prostate cancer development. PIM-1 and PIM-2 over expression in prostate cancer correlates with tumour progression and overexpression of exogenous PIM-1 or PIM-2 in prostate cancer cell lines increases cell proliferation.      

            We have developed a novel small chemical molecule, designated M-110 that is a potent inhibitor of proliferation of a variety of human tumour derived cell lines with little activity on normal human cells.  M-110 is a highly selective inhibitor of the three PIM kinase isoforms, Using M-110 and SGI-1776 (a structurally unrelated PIM inhibitor developed by SuperGen, Inc) and PIM isoform specific knockdown experiments we investigated the involvement of PIM isoforms in the regulation of major proliferative signaling pathways. This established that PIM-3 (but not PIM-2 or PIM-1) is a positive regulator of IL-6/STAT3 signaling in the prostate cancer cell line DU-145 and the pancreatic cell line MiaPaCa2 and that PIM-1 (but not PIM-2 or PIM-3) is a positive co-regulator of EGF/EGFR signaling in DU-145 and PC3 cells. These results define novel  PIM kinase isoform specific biological functions and significantly enhance our understanding of how PIM kinases may regulate cell proliferation.   

            We are now investigating the mechanisms by which PIM-1 positively regulates EGF/EGFR signaling and found that M-110, SGI-1776 and siPIM-1 upregulate the expression of MIG6. This protein binds to the EGFR tyrosine kinase domain and inhibits EGFR signaling. Knockdown of the transcription factor RUNX1 upregulates MIG6 expression, suggesting that RUNX1 is a negative regulator of MIG6 expression. We also showed that PIM-1 phosphorylates recombinant RUNX1 in vitro and that this phosphorylation is inhibited by M-110.  Thus our published and preliminary data suggests that PIM-1 contributes positively to EGFR signaling by suppressing the expression of the EGFR inhibitor MIG6 through phosphorylation of RUNX1.

            Because both PIM inhibitors and EGFR-tyrosine kinase inhibitors (TKIs) inhibit EGFR signaling we tested the hypothesis that PIM inhibitors synergize with the EGFR-TKI Gefitinib to inhibit cell proliferation.  Using the Chou and Talalay method we showed significant synergy between M-110 or SGI-1776 and Gefitinib for inhibition of DU-145 and PC3 cell proliferation.   PIM inhibitors also inhibit the ERK MAPkinase pathway downstream of the EGFR and we showed recently that PIM kinase inhibitors also inhibit activation of MET, the receptor for HGF/SF, downstream of the EGFR.  These are exciting results as they have potential clinical significance by suggesting combination therapies that increase the efficacy of EGFR targeted chemotherapy for late stage prostate cancer patients. 

Best publications:

1.         A. Siu, C.Virtanen and J.Jongstra. PIM kinase isoform specific regulation of MIG6 expression and EGFR signaling in prostate cancer cells. Oncotarget. 2, 1134-1144, 2011.

2.         M.Isaac, A.Siu and J.Jongstra. The oncogenic PIM kinase family regulates drug resistance through multiple mechanisms. Drug Resist Updat. 14, 203-211, 2011.  

 

3.         M.Chang, N.Kanwar, E.Feng, A,Siu, X.Liu, D.Ma and J. Jongstra. PIM kinase inhibitors downregulate STAT3(Tyr705) phosphorylation. Mol Cancer Ther. 9, 2478-2487, 2010.

4.         R.E.Harrison, B.A.Sikorski and J.Jongstra. LSP1 targets the ERK MAPkinase scaffold KSR and MEK1 and ERK2 to the actin cytoskeleton.  J. Cell Sci. 117, 2151-2157, 2004.

5.         M.Y.Cao,  F.Shinjo, S.Heinrichs, J.W.Soh, J.Jongstra-Bilen and J.Jongstra. Inhibition of anti-IgM-induced translocation of protein kinase C beta I inhibits ERK2 activation and increases  apoptosis. J. Biol. Chem. 276,  24506-24510, 2001. 

Work Focus:

  • Work Focus (Biomedical): PIM kinases, combination therapies, drug development, molecular biology, signal transduction pathways

drug development, molecular biology, signal transduction pathways, PIM kinases, combination therapies.

Lab Reagents:

  • Antibodies: Many antibodies against different, and EGFR pathways, anti-LSP1 antibodies, components of the STAT3
  • Cell Lines: Breast cancer cell lines, Colorectal cancer cell lines, Standard prostate cancer cell lines
  • Compounds: Inhibitors of EGFR and c-MET, Inhibitors of the STAT3 pathway, M-110 and other PIM inase inhibitors, small molecule inhibitors:
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