Research Description

Our research focuses on finding cures for Type 1 and Type 2 diabetes.  From a biological perspective, we are interested in understanding how human cells respond to extracellular cues to maintain and ensure their function and survival. A central focus is to better understand how the pancreatic beta cell converts feeding cues into signals leading to insulin synthesis and secretion. We use high-throughput functional genomic imaging screens to identify novel players involved in cell signaling pathways that control human pancreatic beta cell proliferation. In addition, we are interested in the function and quality control of mitochondria, critical subcellular organelles essential for cell function and survival. In addition to Type 1 and Type 2 diabetes, our work impacts upon cancer and neurodegeneration.

Islet Biology
Current work in the lab is directed towards understanding how insulin-producing β cells respond to glucose and cAMP signals and to understand the signaling machinery that regulates β cell proliferation and regeneration. In this regard, we focus on the role of LKB1-AMPK signaling pathway and the CREB coactivator CRTC2. To identify novel gene products and signal transduction mechanisms that are involved in β cell biology, we employ biochemical, cell biological, proteomic and functional genomic approaches, and generate animal models to test the role of these genes in islet function and glucose metabolism in vivo.

Kinomics
Protein phosphorylation regulates virtually all cellular events. Protein kinases and their target proteins control central cell behaviours as proliferation, cell growth, differentiation, innate immunity, cell survival and death, and are of central importance both to basic research and to disease treatment. Identifying kinase substrate pairs, critical nodes in signal transduction pathways, represents a major challenge for understanding how information transfer takes place within a cell. We have developed a kinase screening platform to permit identification of kinase substrate pairs, and used this to elucidate novel pathways involved in glucose sensing. We have also applied the approach to a wide range of biological processes, including mitochondrial dynamics, phagocytosis axon guidance, and stem cell determination.

Cell Based Screening
We employ a state-of-the art robotic cell based screening facility to perform functional genetic screens in mammalian cells to identify novel genes involved in cell function and survival. We are currently performing large scale imaging screens using siRNA technology to identify novel genes that govern the initiation stages of the mitochondrial cell death program, with a view to identifying novel targets for therapeutic intervention for diseases in which inappropriate cell death is a root cause.

Mitochondrial Dynamics
The mitochondrial network is exquisitely sensitive to extracellular signals. Mitochondria becomes hyperfused in response to stress and fragment during cell death. Mitochondrial morphology is largely governed by opposing fission and fusion processes controlled by GTPase molecular switches. However, in mammalian systems, only a few players are known to affect the delicate balance between fragmentation and elongation of the mitochondrial network. Altered mitochondrial dynamics is seen in various disease models ranging from multiple neurodegenerative diseases to diabetes. We are currently using high throughput, high-content screens to identify novel regulators of mitochondrial dynamics, and also evaluating the potential for modulating the network for cancer therapy.

Mitochondrial Integrity
Recent data indicates that mitochondria possess several independent pathways for quality control and integrity, including mitophagy, or autophagic recycling of damaged mitochondria. Parkin, an E3 ubiquitin ligase and a Parkinson’s disease gene, appears to function as a sensor of mitochondrial integrity. We are using a high-throughput, robotic imaging screen to look upstream in this pathway to identify novel genes that control Parkin activity, which may affect its recruitment (i.e. damage sensing or its retention of mitochondria).

Publications

Homozygous mutations in MFN2 cause multiple symmetric lipomatosis associated with neuropathy
Sawyer SL, Ng AC, Innes AM, Wagner JD, Dyment DA, Tetreault M; Care4Rare Canada Consortium, Majewski J, Boycott KM, Screaton R, Nicholson G
Human Molecular Genetics, 2015 Jun 17. pii: ddv229 [Epub ahead of print]  Read

Role of LKB1 in coupling glucose and fatty acid metabolism to insulin secretion
Fu A, Robitaille K, Faubert B, Reeks C, Dai X-Q, Hardy AB, Sankar K, Orgel S, Al-Dirbashi OY, Rocheleau JV, Wheeler MB, MacDonald PE, Jones R, and Screaton RA.
Diabetelogia, 2015 158:1513-22

High-content functional genomic screening to identify novel regulators of the PINK1-Parkin pathway
Ng AC, Baird SD, Screaton RA
Methods in Enzymology, 2014;547:1-20  Read

ROMO1 is an essential redox-dependent regulator of mitochondrial dynamics
Norton M, Ng AC, Baird S, Dumoulin A, Shutt T, Mah N, Andrade-Navarro MA, McBride HM, Screaton RA
Science Signalling, 2014 Jan 28;7(310)  Read

Essential Role of TID1 in Maintaining Mitochondrial Membrane Potential Homogeneity and Mitochondrial DNA Integrity
Ng AC-H, Baird S, Screaton R
Molecular and Cellular Biology, 2014 Apr; 34(8): 1427–1437  Read

Genome-wide RNAi screen identifies ATPase inhibitory factor 1 (ATPIF1) as essential for PARK2 recruitment and mitophagy
Lefebvre V, Du Q, Baird S, Ng AC, Nascimento M, Campanella M, McBride HM, Screaton RA
Autophagy, 2013 Nov 1;9(11):1770-9  Read

CRTC2 is required for β-cell function and proliferation
Eberhard CE, Fu A, Reeks C, Screaton RA
Endocrinology, 2013 Jul;154(7):2308-17  Read

Role of AMPK in pancreatic beta cell function
Fu A, Eberhard CE, Screaton RA
Molecular and Cellular Endocrinology, 2013 Feb 25;366(2):127-34  Read

Loss of Lkb1 in adult beta cells increases beta cell mass and enhances glucose tolerance in mice
Fu A, Ng AC, Depatie C, Wijesekara N, He Y, Wang GS, Bardeesy N, Scott FW, Touyz RM, Wheeler MB, Screaton RA.
Cell Metabolism, 2009 Oct;10(4):285-95  Read

Glucose controls CREB activity in islet cells via regulated phosphorylation of TORC2
Jansson D, Ng AC, Fu A, Depatie C, Al Azzabi M, Screaton RA.
Proceedings of the National Academy of Sciences, 2008 Jul 22;105(29):10161-6  Read

The CREB coactivator TORC2 functions as a calcium- and cAMP-sensitive coincidence detector
Screaton RA1, Conkright MD, Katoh Y, Best JL, Canettieri G, Jeffries S, Guzman E, Niessen S, Yates JR 3rd, Takemori H, Okamoto M, Montminy M
Cell, 2004 Oct 1;119(1):61-74  Read