Professor Rosemary O'Connor
The Insulin/Insulin-like Growth Factor signaling pathway is highly conserved from simple organisms to humans. IGF signaling can be dampened (regulated) to respond to nutrient availability or stress or to enable hibernation. Reduction of IGF signaling increases lifespan in worms, flies and mice. In humans IGF signaling is essential for growth and to maintain tissue function. Intriguingly, while high IGF levels are associated with cancer progression, reduced IGF signaling protects from cancer and diabetes, and may also be associated with longevity. Therefore, an ability to manipulate IGF signaling in specific tissues would have major consequences for prevention of deadly diseases and to enable healthy ageing.
- Regulation of Insulin/IGF-1 Signaling for healthy ageing
- Pdlim2 in cancer metastasis
- IGF-1 and Mitochondrial Function in cancer phenotype
- Biomarkers in IGF pathway
Figure 1. On left: Schematic indicating IGF-1 and Insulin Receptors and ligands, the cellular signalling pathways activated and outcomes; On right top: Model of IGF-1 receptor kinase domain crystal structure indicating C terminal tail residues interacting with the kinase domain; Right bottom: Cartoon demonstrating how c terminal tail interacts with kinase domain
(SFI PI programme)
This research programme is focused on regulation and potential manipulation of IGF signaling at the level of the IGF-1 Receptor. We are using structural and signaling studies with receptor mutants and cell/murine models to determine how kinase activity and signaling output is regulated by intermolecular interactions with the receptor C terminal tail and with cellular proteins that either adapt or suppress signals. Amongst these proteins is the scaffolding protein RACK1, which mediates interactions between IGF-1 and adhesion signaling, cellular kinases and phosphatases.
Kelly, GM., Buckley, DA, Kiely PA, Adams, DR, and O’Connor, R (2012) Serine Phosphorylation of the Insulin-like Growth Factor I Receptor C terminal tail restrains kinase activity and cell growth. J. Biol. Chem. 287: 28180-28194.
Kiely, PA, Baille, GS., Barrett, R, Buckley, DA, Adams, DR, Houslay M and O’Connor R (2009) Phosphorylation of RACK1 on tyrosine 52 by c-Abl is required for the IGF-I-mediated regulation of FAK activity. J. Biol Chem 284: 20263-20274.
Kiely, P. A., D. O'Gorman, K. Luong, D. Ron, and R. O'Connor (2006). Insulin-like growth factor I controls a mutually exclusive association of RACK1 with protein phosphatase 2A and beta1 integrin to promote cell migration. Mol Cell Biol. 26:4041-51
O’Connor, R., Kauffmann-Zeh, A., Liu, Y., Lehar, S., Evan, G.I., Baserga, R., and W.A. Blättler, (1997) Identification of domains of the IGF-IR that are required for protection from apoptosis. Mol. Cell Biol. 17: 427-435.
PDLIM2 associates with and regulates the stability of important transcription factors (STATs NFkB) in epithelial cells, lymphocytes and macrophages. We discovered it in cells that were transformed by over-expression of the IGF-1 Receptor and subsequently in cancer cell lines. PDLIM2 regulates cell fate or differentiation and high expression is associated with control Epithelial Mesenchymal Transition (EMT) or an invasive phenotype in cancer. Our studies are focused on determining the mechanism of action of PDLIM2 in regulating protein stability and in evaluating PDLIM2 as a biomarker for subsets of breast and other cancers.
Deevi, RK, Cox, OT and O’Connor R (2014) Essential function for PDLIM2 in cell polarization in 3 dimensional cultures by feedback regulation of the beta1 integrin RhoA signaling axis. Neoplasia 16: 422-431.
Bowe et al., (2014) PDLIM2 regulates transcription factor activity in Epithelial to Mesenchymal Transition via the Cop9 Signalosome. Mol Biol Cell. 25; 184-195.
Loughran, G., Huigsloot, M, Kiely, P.A., Smith, L.M., Floyd, S., Ayllon, V., and R. O’Connor. (2005) Gene expression associated with IGF-1R-mediated cellular transformation. Oncogene. 24:6185-6193.
Loughran, G., Healy, N., Kiely, P., Kedersha, N., and R. O’Connor (2005) Mystique Is a new Insulin-like Growth Factor-I-regulated PDZ-LIM domain protein that promotes cell attachment and migration and suppresses anchorage-independent growth. Mol. Biol. Cell 16: 1811-1822.
The mitochondrial UTP carrier protein PNC1 (SLC25A33) was originally identified by us as an IGF-1 inducible protein whose expression requires mTOR activity. PNC1 is an orthologue of the yeast RIM2 protein, which is essential for mitochondria DNA and RNA maintenance. Suppression of PNC1 in human cancer cells has a dramatic effect on phenotype leading to invasiveness mediated by ROS signaling. Following these observations we are now investigating how the IGF-1/mTOR pathway contributes to mitochondrial function and maintenance and the importance of this in cancer phenotype and therapy.
Floyd, S., Favre, C., Lasorsa, MS., Leahy,M., Trigiante, G., Stroebel, P., Marx, A., Loughran, G., O’Callaghan, K., Marobbio, C., Slotboom, DJ., Kunji, E., Palmieri, F., and R. O’Connor (2007) The Insulin-like Growth Factor-I mTOR Signaling Pathway Induces the Mitochondrial Pyrimidine Nucleotide Carrier to Promote Cell Growth Mol Biol Cell. 18:3545-3555.
Favre, C, Zhdanov, A, Leahy, M, Papkovsky, D, O'Connor, R; (2010) Pyrimidine Nucleotide Carrier (PNC1) regulates mitochondrial biogenesis and the invasive phenotype of cancer cells. Oncogene 29:3964-3976.
Candidate biomarkers for the IGF pathway that have been identified in functional screen are being evaluated as components of IGF-1 pathway signatures and biomarkers in breast and ovarian cancer.
The heme binding protein HRG-1
Fogarty, F., O’Keeffe, J., Zhdanov, A., Papkovsky, DP, Ayllon, V., and O’Connor, R. (2013) HRG-1 enhances cancer cell invasive potential and couples glucose metabolism to cytosolic/extracellular pH gradient regulation by the Vacuolar H+ ATPase. Oncogene.
Ayllon V and R. O’Connor (2007) PBK/TOPK promotes tumour cell proliferation through p38 MAPK activity and regulation of the DNA damage response. Oncogene 24: 3451-61.
Horizon 2020: The EU Framework Programme for Research and Innovation - Laying down markers for future cancer treatments
Current lab members
Post Doctoral Fellows
Dr Nancy Kedersha (SFI Walton Fellow 2012)
Ms Sandra Ríos Arrabal
University of Granada Spain
The Cell Biology Lab Alumni
Current consortia and collaborations
EU FP7 IAPP programme to identify clinically useful Biomarkers in the IGF signaling pathway, with Almac Diagnostics, Craigavon, Northern Ireland.
Horizon 2020: The EU Framework Programme for Research and Innovation (Laying down markers for future cancer treatments).
Breast Predict: First Irish Cancer Society Collaborative Research Centre focused on breast cancer and involving collaboration between UCD, TCD, RCSI, UCC, NUIG, DCU, ICORG and international collaborations.
Irish Cancer Society Collaborative Research Centre with UCD, TCD, RCSI, NUIG, DCU, ICORG and international collaborations.
Diabetes and cancer
A molecular dissection of the interplay between diabetes and cancer: an integrated, multidisciplinary approach. Medical Research Council UK programme with Professor Marek Brzozowski, University of York, Professor Jiri Jiracek at the Institute of Organic Chemistry & Biochemistry Academy of Sciences of the Czech Republic, and others.
IGF-1 in heart repair
Mechanism of Benefit and Clinical Efficacy of Low Dose Insulin-like Growth Factor-1 in Acute Myocardial Infarct Repair; (HRB/SFI TRA) with Professor Noel Caplice and the Centre for Research in Vascular Biology.
Projects on the RACK1 scaffolding protein and its interactions with the IGF-1R and other signaling proteins in cancer cells and the nervous system with Dr Patrick A. Kiely at University of Limerick, Professor Dorit Ron at UCSF, Dr Nancy Kedersha at Harvard Medical School, Professor Geroge Baille at University of Glasgow. Professor David Adams at Heriot Watt University, and Professor Aideen Long at Trinity College Dublin.
Lab Protocols and Methodologies
Our protocols, plasmids and other reagents are available to share upon request.
Wide range of cell and molecular biology techniques employing generation and expression of proteins, mutant proteins, gene suppression and inducible or stably transfected model cell lines.
Cellular function assays including cell survival, growth, proliferation, invasiveness and tumourigenesis.
Signaling pathway analysis, phosphoprotein analysis, and in vitro kinase assays, siRNA functional screens, RNA profiling, ubiquitination and protein stability analysis.
Protein structure and analysis of protein interactions; including custom peptide arrays for mapping interaction sites, gel filtration, protein expression and purification in prokaryotic and eukaryotic expression systems.