O'Connor group

Professor Rosemary O'Connor

Professor Rosemary O'Connor

About the Cell Biology Research Group

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. 

Current Research Projects in the CB Research Group

  1. Regulation of Insulin/IGF-1 Signaling for healthy ageing
  2. IGF-1 and Mitochondrial Function in cancer phenotype
  3. Pdlim2 in cancer metastasis
  4. Biomarkers in IGF pathway
  5. More ongoing research

1.   Regulation of Insulin/IGF-1 Signaling for healthy ageing

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

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 focuses on the regulation and potential manipulation of IGF signaling at the level of the IGF-1 Receptor and its interactions with cellular kinases, phosphatases and trafficking machinery that control its activity. We use gene editing, mutants and a range of 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 kinase FER which enhances IGF-1 and cell adhesion signalling. A recent significant finding was on IGF-1R transfer to and activity in the Golgi apparatus of migratory cancer cells.

Science Signaling Cover This week (26 May 2020) features a Research Article that shows that translocation of the IGF-1 receptor to the Golgi promotes cancer cell migration. The image shows IGF-1R (green), the cis-Golgi marker GM130 (red), and nuclei (blue) in mouse embryonic fibroblasts in the absence of IGF-1 (upper left) and after stimulation with IGF-1 (lower right). Yellow indicates colocalization of IGF-1R and GM130. [Image: Rieger et al./Science Signaling].

Key Publications

Rieger L, O'Connor R. Controlled Signaling-Insulin-Like Growth Factor Receptor Endocytosis and Presence at Intracellular Compartments. Front Endocrinol (Lausanne). 2021 Jan 29;11:620013. doi: 10.3389/fendo.2020.620013.  

Rieger, L., O’Shea, S., Godsmark, G., Stanicka, J., Kelly, G., and O’Connor, R. (2020) IGF-1 receptor activity in the Golgi of migratory cancer cells depends on adhesion-dependent phosphorylation of Tyr1250 and Tyr1251.  Science Signaling 13: 633 eaba3176 26 May 2020. DOI: 10.1126/scisignal.aba3176 (Subject of cover and focus article in issue)

Stanicka, J., Rieger, L., O’Shea, Cox, OT., Coleman, M., O’Flanagan, C., Addario, B., McCabe, N., Kennedy, R., and O’Connor, R (2018) FES-related Tyrosine Kinase activates Insulin-like Growth Factor 1 Receptor at sites of cell adhesion. Oncogene 27: 3131-3150.

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.

Leahy, M., Lyons,  A., Krause, D, and O’Connor, R. (2004) Impaired Shc, Ras, and MAPK activation, but normal Akt activation in FL5.12 cells expressing an IGF-IR mutated at tyrosines 1250 and 1251. J. Biol. Chem. 279: 18306-18313.

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2.   IGF-1 and Mitochondrial Function in cancer phenotype

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 responses.

Key Publications

Riis, S., Murray, J. B., and O’Connor, R. (2020) IGF-1 Signalling Regulates Mitochondria Dynamics and Turnover through a Conserved GSK-3β–Nrf2–BNIP3 Pathway. Cells Jan 8;9(1). doi: 10.3390/cells9010147.

Lyons, A., Coleman, M., Riis, S., O’Flanagan, F., Zhadanov, A., Favre, C., Papkovsky, D. Hursting. S.D. and O’Connor R.  (2017) IGF-1- signalling is essential for mitochondrial biogenesis and mitophagy in cancer cells. J. Biol. Chem. 292:16983-16998. (Featured in JBC virtual special issue on Cancer: December 2019). 

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.

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.

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3.   Pdlim2 in cancer metastasis

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 levels are associated with Epithelial Mesenchymal Transition  (EMT) or an invasive phenotype in cancer, as we recently demonstrated in Triple Negative Breast Cancer.   Our current studies are focused on evaluating PDLIM2 as a biomarker for subsets of breast and other cancers, and using PDLIM2 knockout mice to investigate its role in cancer progression.

Key Publications

Cox OT, Edmunds SJ, Simon-Keller K, Li B, Moran B, Buckley NE, Bustamante-Garrido M, Healy N, O'Flanagan CH, Gallagher WM, Kennedy RD, Bernards R, Caldas C, Chin SF, Marx A, and  O'Connor R (2019) PDLIM2 Is a Marker of Adhesion and β-Catenin Activity in Triple-Negative Breast Cancer. Cancer Res. 79:2619-2633.

Cox OT, O’Shea S, Tresse E, Bustamante-Garrido M,Kiran-Deevi R and O’Connor R (2015) IGF-1 receptor and adhesion signaling: an important axis in determining cancer cell phenotype and therapy resistance. Front. Endocrinol. 6:106.doi: 10.3389.

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., 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..

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4.   Biomarkers in IGF pathway

A number of candidate biomarkers for the IGF pathway that have been identified in functional screens 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.

PBK TOPK

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

5.   More ongoing research

Key Publications

Stanicka, J., Rieger, L., O’Shea, Cox, OT., Coleman, M., O’Flanagan, C., Addario, B., McCabe, N., Kennedy, R., and O’Connor, R (2018) FES-related Tyrosine Kinase activates Insulin-like Growth Factor 1 Receptor at sites of cell adhesion. Oncogene 27: 3131-3150

Lyons, A., Coleman, M., Riis, S., O’Flanagan, F., Zhadanov, A., Favre, C., Papkovsky, D. Hursting. S.D. and O’Connor R.  (2017) IGF-1- signalling is essential for mitochondrial biogenesis and mitophagy in cancer cells. J. Biol. Chem. 292:16983-16998.

Davies SJ, Ryan J, O'Connor PBF, Kenny E, Morris D, Baranov PV, O'Connor R, McCarthy TV. (2017) Itm2a silencing rescues lamin A mediated inhibition of 3T3-L1 adipocyte differentiation. Adipocyte. 6:259-276.

 

Further information

Biomarker IGF

Biomarker IGF logo. Copyright: Mary Heapes, School of Biochemistry and Cell Biology, University College Cork, Ireland. 2016.

 

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People in the Cell Biology Research Group

Current lab members

Grant Godsmark

Niamh McDermott

Joss Murray

Stephen O'Shea

Stephanie Ward

 

Visiting Scientists

Dr Nancy Kedersha (SFI Walton Fellow 2012)

https://connects.catalyst.harvard.edu/Profiles/display/Person/27772

http://www.vaults.arc.ucla.edu/pages/nancykedersha

 

Ms Sandra Ríos Arrabal
University of Granada Spain

 

The Cell Biology Lab Alumni

Barbara Addario

Janina Berghoff

Verónica Ayllón Cases

Rachael Bowe

Deirdre Buckley

Milan F. Bustamante- Garrido

Noretta Clifford

Michael Coleman

Orla T. Cox

Shelley Edmunds

Cedric Favre

Catherine Fennelly

Isabel Fernández

Suzanne Floyd

Fionola Fogarty

Catherine Harrington

Nollaig Healy

Merei Huigsloot

Andrea Janosch

Geraldine Kelly

Patrick Kiely

Alexander Kingston (visiting student)

Ravi Kiran Deevi

Darren Krause

Madeline Leahy

Gary Loughran

Anthony Lyons

Amy Lyons

Mary McMahon

Katie O’Callaghan

Helen O’Donovan

Ciara O’Flanagan

Jean O'Keeffe

Sandra O’Shea

Badri Rajagopal

Leonie Rieger

Aoife Richardson

Sarah Ris

Loraine Smith

Joanna Stanicka

Sarah Theissen

Emilie Tresse

Melanie Walsh

Patrick Walsh

Collaborations, Links and Cell Biology lab Resources

Current consortia and collaborations

Biomarker IGF

EU FP7 IAPP programme to identify clinically useful Biomarkers in the IGF signaling pathway, with Almac Diagnostics, Craigavon, Northern Ireland.

Almac Group Ltd

Horizon 2020: The EU Framework Programme for Research and Innovation (Laying down markers for future cancer treatments).

Further information on Biomarker IGF...

Biomarker IGF logo. Copyright: Mary Heapes, School of Biochemistry and Cell Biology, University College Cork, Ireland. 2016.

 

BreastPredict

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.

RACK1 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.

School of Biochemistry and Cell Biology

Scoil na Bithcheimice agus na Cillbhitheolaíochta

University College Cork, Western Road, Cork.

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