The Metabolic Signalling Laboratory conducts research on kinase signalling networks that control cellular metabolism. These networks become dysfunctional in metabolic diseases such as insulin resistance, type 2 diabetes and cardiovascular disease, and also represent vulnerabilities in cancer cells that can be targeted to prevent tumour growth and metastasis.

Our principal focus is the cellular fuel gauge AMP-activated protein kinase (AMPK) which detects when energy in the cell is low and co-ordinates multiple pathways to counter energy imbalance (e.g. fat burning, protein synthesis, autophagy). AMPK is also a key regulator of appetite and muscle adaption to exercise. Other metabolic enzymes of interest include CaMKK2, a driver of prostate and ovarian cancers and metabolic disorders, and DRP1, important for mitochondrial health and heart function.

We apply biochemistry, cell biology, microscopy, structural biology, mass spectrometry and animal models to gain insight on the roles of these important enzymes and how they are regulated, with the aim of developing new, effective and safe strategies to unlock their therapeutic potential.

Current research projects

  • mTORC1-AMPK signalling

    AMPK is a serine/threonine protein kinase with central roles in cellular metabolism. AMPK acts as a node for multiple signalling inputs (e.g. phosphorylation, ubiquitination), however understanding of the functional and biological consequences of these modifications is very limited. Expanding on our recent discovery that AMPK is a direct substrate for the mTORC1 kinase, this exciting project will discover new aspects of AMPK regulation that may underpin new treatments for cancer. See Ling et al, Nature Metabolism 2(1):41-49 (2020).

    AMPK drug discovery 1 – small molecule activators

    The metabolic dimensions of type 2 diabetes (T2D), cardiovascular disease, obesity and cancer have driven efforts to progress pharmacological modulators of AMPK to the clinic. Activation of AMPK in skeletal muscle improves glucose control and surgery outcomes in patients with T2D, and could potentially reverse insulin resistance to prevent disease pathogenesis. Working with medicinal chemists at MIPS, this project will drive the development of drugs that specifically activate AMPK isoforms found in skeletal muscle, thereby avoiding adverse effects associated with systemic activators. See Ovens et al, Biochemical Journal 479(11):1181–1204 (2022).

    AMPK drug discovery 2 - small molecule inhibitors

    AMPK becomes hyperactive in a wide range of prevalent human diseases and conditions, including ischemic stroke, neurodegeneration, cancer and viral infection. In ischemic stroke, a life-threatening or debilitating event for many millions worldwide with no immediate therapeutic options, AMPK activation has been linked to excitotoxic shock that damages neurones surrounding the initial ischemic core. We are in a unique position to explore pharmacological AMPK inhibition as a strategy to reduce neuronal damage associated with ischemic stroke. Using cutting-edge phosphoproteomics and inducible mouse models of stroke, this project, supported by the SVI Discovery Fund, will assist in providing proof-of-concept on inhibiting AMPK in the brain to improve patient outcomes and rehabilitation, ultimately leading to a reduction in disease burden for people affected by stroke and their carers. See Hoque et al, Cell Death & Disease 10(3):213 (2019); Dite et al, Journal of Biological Chemistry 293(23):8874–8885 (2018).

    Metabolite regulation of mitochondrial health

    Mitochondria, the powerhouses of the cell, are organelles that provide cells with the essential chemical energy they need for almost all biochemical processes. The mitochondrial network is maintained by a precise equilibrium between fission and fusion events, dysregulation of which leads to poor mitochondrial health associated with many diseases. Our recent discoveries of how the enzyme DRP1 – the effector of mitochondrial fission and a direct AMPK substrate – is directly regulated by lipids opens up exciting avenues for research into DRP1 biology and the effects of obesity on mitochondria. See Rosdah et al, Pharmacology and Therapeutics, 213:107594 (2020).

People

Jon Oakhill
Jon Oakhill

Head, Metabolic Signalling

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+ 61 3 9231 2480

Available for Student Supervision

Sandra Galić

Team leader, Metabolic Physiology

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+ 61 3 9231 2480

Available for Student Supervision

Chris Langendorf

Team leader, Protein Engineering in Immunity & Metabolism

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Available for Student Supervision

Naomi Ling
Naomi Ling

Postdoctoral Senior Research Officer, Metabolic Signalling

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Available for Student Supervision

Ash Hoque
Ashfaqul Hoque

Postdoctoral Senior Research Officer, Metabolic signalling

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Available for Student Supervision

Ashley Ovens

Postdoctoral Research Officer, Protein Engineering in Immunity & Metabolism

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Available for Student Supervision

  • Lisa Murray-Segal, Senior Research Assistant
  • Hamizan Khabib, PhD Student
  • Geoff Zhang, PhD Student
  • Erica Marzi, Honours Student

Student projects

PhD/Masters/Honours

Metabolite regulation of mitochondrial health

Lab: Metabolic Signalling

Supervisor(s): Associate Professor Jon Oakhill

Diseases focus: Healthy Ageing
PhD/Masters/Honours

AMPK drug discovery – small molecule inhibitors

Lab: Metabolic Signalling

Supervisor(s): Associate Professor Jon Oakhill Dr Ashfaqul Hoque

Diseases focus: Healthy Ageing
PhD/Masters/Honours

mTORC1-AMPK signalling

Lab: Metabolic Signalling

Supervisor(s): Associate Professor Jon Oakhill Dr Naomi Ling

Diseases focus: Cancer
Honours

How does fat regulate mitochondrial dynamics?

Lab: Metabolic Signalling

Supervisor(s): Associate Professor Jon Oakhill Dr Ashfaqul Hoque

Diseases focus: Healthy Ageing
Masters/Honours

Examining structure and function of the major drug target AMPK in muscle

Lab: Metabolic Signalling

Supervisor(s): Associate Professor Jon Oakhill

Diseases focus: Healthy Ageing
Honours/Masters

Developing immune cell engagers for cancer therapeutics

Lab: Metabolic Signalling

Supervisor(s): Dr Chris Langendorf

Diseases focus: Cancer
Honours/Masters

Caspase 3 regulation of AMPK

Lab: Metabolic Signalling

Supervisor(s): Dr Chris Langendorf

Diseases focus: Cancer
Honours/Masters

Protein engineered molecules for immune evasion

Lab: Metabolic Signalling

Supervisor(s): Dr Chris Langendorf

Diseases focus: Bioinformatics

Selected publications

Pinkosky SL, Scott JW, Desjardins EM, Smith BK, Day EA, Ford RJ, Langendorf CG, Ling NXY, Nero TL, Loh K, Galic S, Hoque A, Smiles WJ, Ngoei KRW, Parker MW, Yan Y, Melcher K, Kemp BE, Oakhill JS* & Steinberg GR*. Long-chain fatty acyl-CoA esters regulate metabolism via allosteric control of AMPK beta1 isoforms. *co-senior authors. Nature Metabolism, 2(9):873-881 (2020). DOI: 10.1038/s42255-020-0245-2

Ling NXY, Kaczmarek A, Hoque A, Davie E, Ngoei KRW, Morrison KR, Smiles WJ, Forte GM, Wang T, Lie S, Dite TA, Langendorf CG, Scott JW, Oakhill JS* & Petersen J*. mTORC1 directly inhibits AMPK to promote cell proliferation under nutrient stress. *co-senior authors. Nature Metabolism, 2(1):41-49 (2020). DOI: 10.1038/s42255-019-0157-1

Dite TA, Langendorf CG, Hoque A, Galic S, Rebello RJ, Ovens AJ, Lindqvist LM, Ngoei KRW, Ling NXY, Furic L, Kemp BE, Scott JW & Oakhill JS. AMP-activated protein kinase selectively inhibited by the type II inhibitor SBI-0206965. Journal of Biological Chemistry, 293:8874-8885 (2018). DOI: 10.1074/jbc.RA118.003547

Ngoei KRW, Langendorf CG, Ling NXY, Hoque A, Varghese S, Camerino MA, Walker SR, Bozikis YE, Dite TA, Ovens AJ, Smiles WJ, Jacobs R, Huang H, Parker MW, Scott JW, Rider MH, Foitzik RC, Kemp BE, Baell JB & Oakhill JS. Structural Determinants for Small-Molecule Activation of Skeletal Muscle AMPK α2β2γ1 by the Glucose Importagog SC4. Cell Chemical Biology, 25:728-737 (2018). DOI: 10.1016/j.chembiol.2018.03.008

Dite TA, Ling NXY, Scott JW, Hoque A, Galic S, Parker BL, Ngoei KRW, Langendorf CG, O’Brien MT, Kundu M, Viollet B, Steinberg GR, Sakamoto K, Kemp BE, Oakhill JS. The autophagy initiator ULK1 sensitizes AMPK to allosteric drugs. Nature Communications, 8:571 (2017). DOI: 10.1038/s41467-017-00628-y

Oakhill JS, Steel R, Chen ZP, Scott JW, Ling N, Tam S & Kemp BE. AMPK is a direct adenylate charge-regulated protein kinase. Science, 332:1433-1435 (2011). DOI: 10.1126/science.1200094

ORCID profile: 0000-0002-9475-1440

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