Ng Lab - Kinase biology

We are a molecular cell biology group with a primary interest in defining how cells respond to extrinsic and intrinsic signals to define cell function. In particular, our research is focused on intracellular kinases such as the mitogen-activated protein kinase (MAPK) family that catalyze post-translational phosphorylation modifications on a diverse range of substrates, that include cytoskeletal proteins and transcription factors. These signalling mechanisms are central for initiating and maintaining the fidelity of key cellular processes such as duplication (mitosis), cell death (apoptosis) or fate specification (differentiation). Defects or disruption of these regulatory mechanisms are molecular drivers of human disease which exemplifies the importance of defining how these signalling mechanisms are assembled and orchestrated.

We are particularly interested in how dysregulated kinase signalling can contribute to birth defects associated with rare genetic disorders such as primary microcephaly and the pathology of age-related diseases such as heart failure, cancer and neurodegeneration. Our goal is to provide detailed mechanistic understanding of what goes wrong in disease at the molecular and cellular level with the expectation that this knowledge may trigger new developments or strategies for disease therapy.

Research keywords:

Intracellular Signal Transduction, Mitogen-activated protein kinases, Cytoskeleton, Tissue growth, Cell Division, Cell Survival, Cell Death and Cell Fate Specification.

Lab head

Staff

Students

Discover how MAPKs regulate microtubules through tubulin-binding proteins

This project extends our work on the tubulin-associated stathmin (STMN) family of phosphoproteins as key downstream effectors directly linking kinase activity with microtubule dynamics. Stathmin family proteins negative regulate microtubule polymerization by binding and sequestering monomers (ie. a/b tubulin). Their regulated activity contributes greatly to dynamic nature of microtubules in all cell types. Stathmin-regulated microtubules in neurons control synaptic activity translating into learning and memory. Hyperactivation and overexpression of STMN accelerates cancer cell proliferation and migration to significantly worsen patient prognosis in a broad range of cancer types. Defining the MAPK-STMN signalling relationship is therefore of high importance to human health.

Structure of stathmin
Structure of stathmin bound to four a/b tubulin subunits. STMN interactions with tubulins are kinase-regulated and contribute to dynamic equilibrium of tubulin monomers to polymers (ie microtubules)
STMN has microtubule destabilizing activity
STMN has microtubule destabilizing activity and overexpression disrupts microtubules in cells (adapted from Yip et al. 2014).

Collaborators

  • Maria Kavallaris (Children’s Cancer Institute, NSW)
  • Heung-Chin Cheng (Biochemistry and Molecular Biology, University of Melbourne)
  • David Simmons (SBMS, UQ)

Related publications

1. Fife, C.M., Sagnella, S.M., Teo, W.S., Po'uha, S.T., Byrne, F.L., Yeap, Y.Y., Ng, D.C.H., Davis, T.P., McCarroll, J.A. and Kavallaris, M. 2016

Stathmin mediates neuroblastoma metastasis in a tubulin-independent manner via RhoA/ROCK signaling and enhanced transendothelial migration.

Oncogene, doi: 10.1038/onc.2016.220.

2. Yip, Y.Y., Yeap, Y.Y., Bogoyevitch, M.A. & Ng, D.C.H. 2014.

cAMP-dependent protein kinase and c-Jun N-terminal kinase mediate stathmin phosphorylation for the maintenance of interphase microtubules during osmotic stress.

J Biol Chem, 289, 2157-69.

3. Ng, D.C.H. and Byrne, F. 2012.

“Stathmin and cancer.” Chapter 14, 259-284. Book Title: The Cytoskeleton and Human Disease. Kavallaris M. [Ed.]. Spinger Press, NY, USA.

Probing the role of kinase signalling scaffold proteins in normal brain growth

Scaffolds proteins interact with kinases to assemble distinct signalling modules for exquisite spatiotemporal control of phosphorylation activity. Our lab recently characterized a c-Jun N-terminal kinase (JNK) binding protein, WDR62, as a microtubule-associated scaffold protein required to direct phosphorylation at the bipolar mitotic spindle to control cell division and differentiation of neural stem and progenitor cells. WDR62 mutations are causative of human primary microcephaly, a birth defect characterized by severely reduced head and brain size. This highlights the importance of WDR62-regulated signalling events in human brain development. This project will probe how WDR62 controls neural stem cell proliferation, fate commitment and brain growth using defined model systems.

WDR62
WDR62 is a kinase-associated scaffold protein localized to the mitotic spindle poles. It’s functions here are required for normal brain development in humans (adapted from Lim et al. 2015).
Drosophila larval brains
Drosophila larval brains. This project take advantage of excellent model systems such as the developing fly brain as an in vivo model to study neural stem cell renewal and differentiation. Findings are further translated to mouse embryos as a mammalian model of neurodevelopment (unpublished from Lim NR).

Collaborators

  • Zhiheng Xu (Chinese Academy of Science, Beijing, China)
  • Marie Bogoyevitch (Biochemistry and Molecular Biology, University of Melbourne)
  • Leonie Quinn (John Curtin School of Medical Research, ANU)
  • Sean Millard (SBMS, UQ)
  • Michael Piper (SBMS, UQ)

Related publications

1. Lim, N.R., Yeap, Y.Y., Ang, C-S., Williamson, N.A., Bogoyevitch, M.A., Quinn, L.M. and Ng, D.C.H. 2016.

Aurora A phosphorylation of WD40-repeat protein 62 for mitotic spindle regulation.

Cell Cycle, 15:413-424

2. Lim, N.R., Yeap, Y.Y., Zhao, T.T., Yip, Y.Y., Wong, S.C., Xu, D., Ang, C.S., Williamson, N.A., Xu, Z., Bogoyevitch, M.A. & Ng, D.C.H. 2015.

Opposing roles for JNK and Aurora A in regulating WD40-Repeat Protein 62 association with spindle microtubules.

J Cell Sci, 128, 527-540

3. Bogoyevitch, M.A., Yeap, Y.Y., Qu, Z., Ngoei, K.R., Yip, Y.Y., Zhao, T.T., Heng, J.I. and Ng, D.C.H. 2012.

WD40-repeat protein 62 is a JNK-phosphorylated spindle pole protein required for spindle maintenance and timely mitotic progression.

J Cell Sci, 125, 5096-109.

Reveal how centrosome signalling controls cell fate

Centrosomes are an enigmatic membrane-less, protein-dense organelles that co-ordinate intracellular signalling and cytoskeleton organization.  At its core, centrosomes are comprised of a pair of asymmetric tubulin barrels (centrioles) that are differentially segregated in self-renewing pluripotent stem cells. Multiple intracellular kinases are concentrated at centrosomes to form a signalling hub that is essential for cell cycle regulation, division orientation and cortical polarity. Thus, centrosome structure and function is intimately involved in maintaining proliferating stem cells and the fate commitment and differentiation of their progeny. This project will utilize myocytes and neurons from human pluripotent embryonic stem cells to investigate how centrosomal kinases control cell fate in neural and cardiac systems.

Centrosomes (magenta) in an immature dividing cardiac myocyte
Centrosomes (magenta) in an immature dividing cardiac myocyte. Centrosome function is required to maintain the proliferative capacity of immature embryonic myocytes (unpublished image from Hannah Perks and Dominic Ng).

Collaborators

  • James Hudson (SBMS, UQ)
  • Mirella Dottori (Department of Neural Engineering, University of Melbourne)

Mapping MAPK signalling pathways in the heart

Cardiovascular disease, encompassing myocardial infarction and heart failure, is the leading cause of worldwide mortality (12.8% of all deaths) and contributes significantly to the escalating health care expenditure and disease burden in most developed nations. Mitogen-activated protein kinases mediate protective and compensatory responses in the heart but paradoxically, hyperactivation of certain family members can trigger cardiac cell death to exacerbate myocardial injury and significantly increase the risk of heart failure. This project will delineate the protective versus detrimental effects of MAPK signalling pathways in the heart to better define kinase-targeting drug therapy for cardioprotection or ameliorate heart failure progression in the clinic.

Signalling mechanisms that regulate cardiomyocyte survival and myocardial injury
Signalling mechanisms that regulate cardiomyocyte survival and myocardial injury.

Collaborators

  • Owen Woodman (School of Health and Biomedical Science, RMIT)
  • Melissa Reichelt (SBMS, UQ)

Related publications

1. Lim, N.R., Thomas, C.J., Silva, L.S., Yeap, Y.Y., Yap, S., Bell, J.R., Delbridge, L.M., Bogoyevitch, M.A., Woodman, O.L., Williams , S.J., May, C.N. and Ng, D.C.H. 2013.

Cardioprotective 3',4'-dihydroxyflavonol attenuation of JNK and p38(MAPK) signalling involves CaMKII inhibition.

Biochem J, 456, 149-61.

2. Ng, D.C.H., Ng, I.H., Yeap, Y.Y., Badrian, B., Tsoutsman, T., McMullen, J.R., Semsarian, C. and Bogoyevitch, M.A. 2011.

Opposing actions of extracellular signal-regulated kinase (ERK) and signal transducer and activator of transcription 3 (STAT3) in regulating microtubule stabilization during cardiac hypertrophy.

J Biol Chem, 286, 1576-87.

2016

Fife, C.M., Sagnellla, S.M., Teo, W.S., Po'uha, S.T., Byrne, F.L., Yeap, Y.Y., Ng, D.C.H., Davis, T.P., McCarroll, J.A. and Kavallaris, M. 2016
Stathmin mediates neuroblastoma metastasis in a tubulin-independent manner via RhoA/ROCK signaling and enhanced transendothelial migration.
Oncogene, doi: 10.1038/onc.2016.220.

Hoque, A., Hossain, M.I., Ameen, S., Ang, C-S., Williamson, N.A., Ng, D.C.H., Chueh, A.C., Roulston, C. and Cheng, H-C. 2016.
A Beacon of Hope in Stroke Therapy – Blockade of Pathological Cellular Events Leading to Excitotoxic Neuronal Death as a Neuroprotective Strategy.
Pharmacol Ther, 160, 159-79. Review

Lim, N.R., Yeap, Y.Y., Ang, C-S., Williamson, N.A., Bogoyevitch, M.A., Quinn, L.M. and Ng, D.C.H. 2016.
Aurora A phosphorylation of WD40-repeat protein 62 for mitotic spindle regulation.
Cell Cycle, 15:413-424

2015

Birnie, K.A., Yip, Y.Y., Ng, D.C.H., Kirschner, M.B., Reid, G., Prele, C.M., Musk, A.W., Lee, Y.G., Thompson, P.J., Mutsaers, S.E. and Badrian, B. 2015.
Loss of mir-223 and JNK Signalling Contribute to Elevated Stathmin in Malignant Pleural Mesothelioma.
Mol Cancer Res. 13:1106-1118.

Thomas, C.J., Lim, N.R., Kedikaetswe, A., Yeap, Y.Y., Woodman, O.L., Ng, D.C.H. and May, C.N. 2015.
Evidence that the MEK/ERK but not the PI3K/Akt pathway is required for protection from myocardial ischemia-reperfusion injury by 3',4'-dihydroxyflavonol.
Eur J Pharmacol. 758:53-59.

Bell, J.R., Raaijmakers, A. J., Curl, C.L., Reichelt, M.E., Harding, T.W., Bei, A., Ng, D.C.H., Erickson, J.R., Vila Petroff, M., Harrap, S.B. & Delbridge, L.M. 2015.
Cardiac CaMKIIdelta splice variants exhibit target signaling specificity and confer sex-selective arrhythmogenic actions in the ischemic-reperfused heart.
Int J Cardiol, 181, 288-96.

Lim, N.R., Yeap, Y.Y., Zhao, T.T., Yip, Y.Y., Wong, S.C., Xu, D., Ang, C.S., Williamson, N.A., Xu, Z., Bogoyevitch, M.A. & Ng, D.C.H. 2015.
Opposing roles for JNK and Aurora A in regulating WD40-Repeat Protein 62 association with spindle microtubules.
J Cell Sci, 128, 527-540

Iqbal Hossain, M., Hoque, A., Lessene, G., Aizuddin Kamaruddin, M., Chu, P.W., Ng, I.H., Irtegun, S., Ng, D.C.H., Bogoyevitch, M.A., Burgess, A.W., Hill, A.F. & Cheng, H-C. 2015.
Dual role of Src kinase in governing neuronal survival.
Brain Res, 1594, 1-14.

2014

Yip, Y.Y., Yeap, Y.Y., Bogoyevitch, M.A. & Ng, D.C.H. 2014.
cAMP-dependent protein kinase and c-Jun N-terminal kinase mediate stathmin phosphorylation for the maintenance of interphase microtubules during osmotic stress.
J Biol Chem, 289, 2157-69.

Yip, Y.Y., Yeap, Y.Y., Bogoyevitch, M.A. & Ng, D.C.H. 2014.
Differences in c-Jun N-terminal kinase recognition and phosphorylation of closely related stathmin-family members.
Biochem Biophys Res Commun, 446, 248-54.

Misheva, M., Kaur, G., Ngoei, K.R., Yeap, Y.Y., Ng, I.H., Wagstaff, K.M., Ng, D. C. H., Jans, D.A. & Bogoyevitch, M. A. 2014.
Intracellular mobility and nuclear trafficking of the stress-activated kinase JNK1 are impeded by hyperosmotic stress.
Biochim Biophys Acta, 1843, 253-64.

2013

Lim, N.R., Thomas, C.J., Silva, L.S., Yeap, Y.Y., Yap, S., Bell, J.R., Delbridge, L.M., Bogoyevitch, M.A., Woodman, O.L., Williams , S.J., May, C.N. and Ng, D.C.H. 2013.
Cardioprotective 3',4'-dihydroxyflavonol attenuation of JNK and p38(MAPK) signalling involves CaMKII inhibition.
Biochem J, 456, 149-61.

Hossain, M.I., Roulston, C.L., Kamaruddin, M.A., Chu, P.W., Ng, D.C.H., Dusting, G.J., Bjorge, J.D., Williamson, N.A., Fujita, D.J., Cheung, S.N., Chan, T.O., Hill, A.F. and Cheng, H-C. 2013.
A truncated fragment of Src protein kinase generated by calpain-mediated cleavage is a mediator of neuronal death in excitotoxicity.
J Biol Chem, 288, 9696-709.

Ngoei, K.R., Ng, D.C.H., Gooley, P.R., Fairlie, D.P., Stoermer, M.J. and Bogoyevitch, M.A. 2013.
Identification and characterization of bi-thiazole-2,2'-diamines as kinase inhibitory scaffolds.
Biochim Biophys Acta, 1834, 1077-88.

2012

Ng, I.H., Ng, D.C.H., Jans, D.A. and Bogoyevitch, M.A. 2012.
Selective STAT3-alpha or -beta expression reveals spliceform-specific phosphorylation kinetics, nuclear retention and distinct gene expression outcomes.
Biochem J, 447, 125-36.

Bogoyevitch, M.A., Yeap, Y.Y., Qu, Z., Ngoei, K.R., Yip, Y.Y., Zhao, T.T., Heng, J.I. and Ng, D.C.H. 2012.
WD40-repeat protein 62 is a JNK-phosphorylated spindle pole protein required for spindle maintenance and timely mitotic progression.
J Cell Sci, 125, 5096-109.

Ramdzan, Y.M., Polling, S., Chia, C.P., Ng, I.H., Ormsby, A.R., Croft, N.P., Purcell, A.W., Bogoyevitch, M.A., Ng, D.C.H., Gleeson, P.A. and Hatters, D.M. 2012.
Tracking protein aggregation and mislocalization in cells with flow cytometry.
Nat Methods, 9, 467-70.

Ng, D.C.H. and Byrne, F. 2012.
“Stathmin and cancer.” Chapter 14, 259-284. Book Title: The Cytoskeleton and Human Disease. Kavallaris M. [Ed.]. Spinger Press, NY, USA.

2011

Meyerowitz, J., Parker, S.J., Vella, L.J., Ng, D.C.H., Price, K.A., Liddell, J.R., Caragounis, A., Li, Q.X., Masters, C.L., Nonaka, T., Hasegawa, M., BOogoyevitch, M.A., Kanninen, K.M., Crouch, P.J. and White, A.R. 2011.
C-Jun N-terminal kinase controls TDP-43 accumulation in stress granules induced by oxidative stress.
Mol Neurodegener, 6, 57.

Waardenberg, A.J., Bernardo, B.C., Ng, D.C.H., Shepherd, P.R., Cemerlang, N., Sbroggio, M., Wells, C. A., Dalrymple, B.P., Brancaccio, M., Lin, R.C. and McMullen, J.R. 2011.
Phosphoinositide 3-kinase (PI3K(p110alpha)) directly regulates key components of the Z-disc and cardiac structure.
J Biol Chem, 286, 30837-46.

Thomas, C.J., Ng, D.C.H., Patsikatheodorou, N., Limengka, Y., Lee, M.W., Darby, I.A., Woodman, O. L. and May, C.N. 2011.
Cardioprotection from ischaemia-reperfusion injury by a novel flavonol that reduces activation of p38 MAPK.
Eur J Pharmacol, 658, 160-7.

Ngoei, K.R., Catimel, B., Church, N., Lio, D.S., Dogovski, C., Perugini, M.A., Watt, P.M., Cheng, H-C., Ng, D.C.H. and Bogoyevitch, M.A. 2011.
Characterization of a novel JNK (c-Jun N-terminal kinase) inhibitory peptide.
Biochem J, 434, 399-413.

Ng, D.C.H., Ng, I.H., Yeap, Y.Y., Badrian, B., Tsoutsman, T., McMullen, J.R., Semsarian, C. and Bogoyevitch, M.A. 2011.
Opposing actions of extracellular signal-regulated kinase (ERK) and signal transducer and activator of transcription 3 (STAT3) in regulating microtubule stabilization during cardiac hypertrophy.
J Biol Chem, 286, 1576-87.

2010

Ng, D.C.H., Zhao, T.T., Yeap, Y.Y., Ngoei, K.R. and Bogoyevitch, M.A. 2010.
c-Jun N-terminal kinase phosphorylation of stathmin confers protection against cellular stress.
J Biol Chem, 285, 29001-13.

Yeap, Y.Y., Ng, I.H., Badrian, B., Nguyen, T.V., Yip, Y.Y., Dhillon, A.S., Mutsaers, S.E., Silke, J., Bogoyevitch, M.A. and Ng, D.C.H. 2010.
c-Jun N-terminal kinase/c-Jun inhibits fibroblast proliferation by negatively regulating the levels of stathmin/oncoprotein 18.
Biochem J, 430, 345-54.

Ng, D.C.H., Lim, C.P., Lin, B.H., Zhang, T. and Cao, X. 2010.
SCG10-like protein (SCLIP) is a STAT3-interacting protein involved in maintaining epithelial morphology in MCF-7 breast cancer cells.
Biochem J, 425, 95-105.

Bogoyevitch, M.A., Ngoei, K.R., Zhao, T.T., Yeap, Y.Y. and Ng, D.C.H. 2010.
c-Jun N-terminal kinase (JNK) signaling: recent advances and challenges.
Biochim Biophys Acta, 1804, 463-75. Review

Lab alumni

  • Dr Nicholas Rui Lim

Former Honours and PhD student. 2012-2016 - Postdoctoral Research Fellow at Duke-NUS, Singapore.

  • Dr Yan Yan Yip

Former PhD student. 2012-2015 - Postdoctoral Research Fellow at Kings College London, UK.

  • Mr Lokugan Silva

Former MSc student. 2013-2014 - PhD candidate at Peter McCallum Cancer Centre.

  • Miss Teresa Tian Zhao

Former MSc student. 2009-2010 - Research Officer at Dept of Pathology, University of Melbourne.

  • Miss Wen Fang Ong

Former Honours student 2016 - Relaxing in Singapore

  • Mr Navin Mitter

Former Honours student 2016 - Relaxing in Singapore

  • Mr Andrew Danyluk

Former Honours student (First Class) 2014 - In medical school studying for his MD.

Funding

The lab acknowledges research support from the following organizations:

  • National Health and Medical Research Council
  • Australian Research Council
  • The Robert Baillie Research Grant (Cancer Council Queensland)
  • ANZ Charitable Trusts
  • National Heart Foundation of Australia
  • SBMS-UQ
  • Neuprotect Pty Ltd

Society memberships and activities

  • Long standing member of Australian Society for Biochemistry and Molecular Biology (ASBMB), Australian and New Zealand Society for Cell and Developmental Biology (ANZSCDB) and the International Society for Heart Research (ISHR).
  • ComBio2016 Overall Program Chair and Secretary for Local Organizing Committee.
  • ASBMB Queensland State Representative (2015 - )
  • ASBMB representative for Science Meets Parliament (2011).
  • “State News” associate editor for the “Australian Biochemist” (ASBMB).
  • Annual Queensland Science Contest (Science Teachers Association of Queensland).

Research recognition

  • Dyason Fellowship (2013)
  • Australian Research Council Future Fellowship (2013)
  • The Life Technologies Edman Award (2011)
  • Bioplatforms Australia Award (2011)
  • International Federation of Cell Biology (IFCB) Fellowship (2009)
  • Bendat Family Foundation Fellowship Award (2007)
  • National Health and Medical Research Council Peter Doherty Fellowship (2006).
  • Biochemical Journal’s Young Investigator Award (2006)
  • Australian Society of Biochemistry and Molecular Biology Fellowship (2003)
  • Promega Manuscript Prize (2001)
  • Swan Brewery Prize in Biochemistry (1999)
  • Lugg Medal (1998)

Find out more about our research environment and how to apply to do a short or long-term research project with us.