Protein-metabolites interaction networks in biological systems
Proteins act in complex networks with other macromolecules (other proteins, DNA, RNA) or with metabolites (interactomes). Such networks are essential to all biological processes and functions and their alteration can often lead to disease.
Protein-metabolite interactomes are poorly characterised and the current challenge is to map, on a large scale, protein networks in a spatial and temporal manner and to further analyse how they are differently regulated in various physiological processes.
Our lab focuses on protein-phospholipid interaction networks and in particular on nuclear protein-polyphosphoinositide complexes. Polyphosphoinositides (PPIn) are lipid signalling molecules regulating a vast array of cellular functions via their interaction with diverse proteins. Most research has focused on their cytoplasmic functions. PPIn are however also present in the nucleus but their functions are still poorly understood.
T Karlsson, C Krakstad, IL Tangen, EA Hoivik, PM Pollock, HB Salvesen & AE Lewis (2017). Endometrial cancer cells exhibit high expression of p110b and variable response to both p110a and p110b inhibition on PI3K signalling, cell survival and proliferation. Oncotarget. 8:3881-94.
Mjos S, Werner HMJ, Birkeland E, Holst F, Berg A, Halle MK, Tangen IL, Kusonmano K, Mauland KK, Oyan AM, Kalland KH, Lewis AE, Mills GB, Krakstad C, Trovik J, Salvesen HB, Hoivik EA (2017). PIK3CA exon9 mutations associate with reduced survival, and are highly concordant between matching primary tumors and metastases in endometrial cancer. Sci. Reports. 7(1):10240. doi: 10.1038/s41598-017-10717-z.
Jacobsen RM, Gavgani FM, Mellgren G and AE Lewis (2016). DNA Topoisomerase IIa contributes to the early steps of adipogenesis in 3T3-L1 cells. Cellular Signalling. 28:1593-1603.
T Karlsson, A Altanchimeg, O Dobrovolska, DC Turcu and AE Lewis (2016). A polybasic motif in ErbB3-Binding-Protein 1 (EBP1) has key functions in nucleolar localisation and polyphosphoinositide interaction. Biochemical Journal. 473: 2033-47. DOI: 10.1042/BCJ20160274.
AE Lewis, R Aesoy and M Bakke. (2016). Role of EPAC in cAMP-mediated actions in adrenocortical cells. Frontiers in Endocrinology, Neuroendocrine Science. Invited Mini-Review. doi 10.3389/fendo.2016.00063.
CS D’Santos and AE. Lewis (2012). Functional Proteomics: Mapping Lipid-Protein Interactomes. Book Chapter. Integrative Proteomics, Hon-Chiu Eastwood Leung (Ed.), ISBN: 978-953-51-0070-6, InTech, Available from: http://www.intechopen.com/articles/show/title/functional-proteomics-mapp...
AE Lewis, L Sommer, MØ Arntzen, Y Strahm, NA Morrice, N Divecha and CS D’Santos (2011). Identification of nuclear phosphatidylinositol 4,5-bisphosphate-interacting proteins by neomycin extraction. Molecular & Cellular Proteomics. 10(2):M110.003376. IF: 8.8
L Aumo, M Rusten, G Mellgren, M Bakke and AE Lewis (2010). Functional roles of PKA and EPAC2 in cAMP-mediated actions in adrenocortical cells. Endocrinology. 151:2151-61.IF: 4.94.
VV Ardawatia, M Masià-Balagué, BF Krakstad, BB Johansson, KM Kreitzburg, E Spriet, AE Lewis, TE Meigs, AM Aragay (2010). Gα(12) binds to the N-terminal regulatory domain of p120(ctn), and downregulates p120(ctn) tyrosine phosphorylation induced by Src family kinases via a RhoA independent mechanism. Exp. Cell Res. in press 2010 Oct 22. IF: 3.59
EA Hoivik, AE Lewis, L Aumo and M Bakke (2009). Molecular aspects of steroidogenic factor 1 (SF-1). Review. Molecular Cellular Endocrinology.315:27-39. IF: 3.61.
MØ Arntzen, CL Osland, CR Raa, R Kopperud, SO Døskeland, AE Lewis and CS D’Santos (2009). POSTMan (POST-translational Modification analysis), a software application for PTM discovery. Proteomics. 9:1400-6. IF: 4.59.
Hoivik EA, Aumo L, Aesoy R, Lillefosse H, Lewis AE, Perrett RM, Stallings NR, Hanley NA, Bakke M (2008). Deoxyribonucleic Acid methylation controls cell type-specific expression of steroidogenic factor 1. Endocrinology. 149:5599-609. IF: 4.94.
AE Lewis, M Rusten, EA Hoivik, EL Vikse, ML Hansson, AE Wallberg, and M Bakke (2008). Phosphorylation of Steroidogenic Factor 1 Is Mediated by Cyclin-Dependent Kinase 7. Molecular Endocrinology. 22: 91–104. IF: 5.39.
AJ Fikaris,AE Lewis, A Abulaiti, O Tsygankova and JL Meinkoth (2006). Ras triggers ATR activation and apoptosis through sustained mitogenic signaling. J. Biol. Chem. 281:34759-67. IF: 5.52.
AE Lewis, AJ Fikaris, G Prendergast and JL Meinkoth. (2004). TSH and serum regulate thyroid cell proliferation through differential effects on p27 expression and localization. Molecular Endocrinology. 18: 2321-2332. IF: 5.39.
AE Lewis, BCY Wong, MJS Langman and MC Eggo. (2004). Protein kinase C delta is not activated by caspase-3 and its inhibition is sufficient to induce apoptosis in the colon cancer line, COLO 205. Cellular Signalling. 17: 253-262. IF: 4.3.
G Cheng, AE Lewis and JL Meinkoth. (2003). Ras stimulates aberrant cell cycle progression and apoptosis in rat thyroid cells. Molecular Endocrinology. 17: 450-459. IF: 5.39.
AE Lewis, BCY Wong, MJS Langman and MC Eggo. (2003). Protein kinase C inhibition induces DNA fragmentation in Colo 205 cells, which is blocked by cysteine protease inhibition but not mediated through caspase-3. Experimental Cell Research. 289: 1-10. IF: 3.95.
Y Qiu, CE Waters, AE Lewis, MJ Langman and MC Eggo. (2002). Oestrogen-induced apoptosis in colonocytes expressing oestrogen receptor b. Journal of Endocrinology. 174: 369-377. IF: 2.79.
S Dearn, M Rahman, A Lewis, Z Ahmed, MC Eggo and AS Ahmed. (2000). Activation of platelet-activating factor (PAF) receptor stimulates nitric oxide (NO) release via protein kinase C-α in HEC-1B human endometrial epithelial cell line. Molecular Medicine. 6: 37-49. IF: 3.41.
- 2019. Polyphosphoinositides in the nucleus: Roadmap of their effectors and mechanisms of interaction. Advances in Biological Regulation. 72: 7-21. doi: 10.1016/j.jbior.2019.04.001
- 2018. Class I Phosphoinositide 3-Kinase PIK3CA/p110α and PIK3CB/p110β Isoforms in Endometrial Cancer. International Journal of Molecular Sciences. 19. doi: 10.3390/ijms19123931
- 2017. Endometrial cancer cells exhibit high expression of p110β and its selective inhibition induces variable responses on PI3K signaling, cell survival and proliferation. OncoTarget. 8: 3881-3894. Published 2017-01-17. doi: 10.18632/oncotarget.13989
- 2017. PIK3CA exon9 mutations associate with reduced survival, and are highly concordant between matching primary tumors and metastases in endometrial cancer. Scientific Reports. 7:10240: 1-12. doi: 10.1038/s41598-017-10717-z
- 2016. A polybasic motif in ErbB3-binding protein 1 (EBP1) has key functions in nucleolar localization and polyphosphoinositide interaction. Biochemical Journal. 473: 2033-2047. doi: 10.1042/BCJ20160274
Dr Olena Dobrovolska - Postdoc
Victoria Smith Arnesen - master student
Jamil Shafayat - master student
Identifying phosphoinositide interacting nuclear proteins to understand their function:
Using a quantitative proteomic methods to enrich for and identify nuclear phosphoinositide effector proteins. Using this method, we have identified nuclear proteins interacting with phosphatidylinositol (4,5) bisphosphate (PtdIns(4,5)P2) (PubMed ID 21048195) and PtdIns(3,4,5)P3, two of the 7 existing PIs.
Current projects include further analysis of these potential interactions (PubMed ID 27118868)
- Biochemical validation of the interactions
- Role of PtdIns(4,5)P2 and PtdIns(3,4,5)P3 in the function of these proteins
- Mechanism of regulation of these interactions
- Effect of PtdIns(4,5)P2 and PtdIns(3,4,5)P3 on protein structure
Mapping changes in protein-phosphoinositide interactomes in pathological states
Our current goal is to map which protein-phosphoinositide networks are remodelled in pathological states where the phosphoinositide metabolic pathways are known to be altered (e.g. obesity, type 2 diabetes mellitus, cancer).
Long term goal: To design small molecules disrupting specific protein-phosphoinositide interactions found to be altered in these diseases.
To determine the nuclear role of the PI3K pathway in cancer development