- Roles of centrosome overamplification in carcinogenesis
- Rho GTPases signaling in cancer metastasis
- Neuronal cell differentiation and migration
- Assistant Professor, Department of Anatomy, The University of Hong Kong, Hong Kong
- Research Assistant Professor, Department of Pathology and Biochemistry, The University of Hong Kong, Hong Kong
- Postdoctoral fellow, Institute of Molecular Biology, The University of Hong Kong, Hong Kong
- Research Associate, Department of Biochemistry, Hong Kong University of Science and Technology, Hong Kong
- Ph.D., Dundee University, UK
- B.Sc., Imperial College, University of London, UK
- Member, Centre for Cancer Research, The University of Hong Kong
- Honorary Principal Investigator, State Key Laboratory of Brain and Cognitive Sciences
- Principal Investigator, State Key Laboratory for Liver Research
- Honorary Assistant Professor, Department of Pathology, The University of Hong Kong, Hong Kong
Neuronal Cdc2-like kinase (Nclk)
Neuronal cdc2-like kinase (Nclk) has been shown to play an important role in neuronal differentiation, neuro-cytoskeleton dynamics, and neurite extension. Aberrant of Nclk activity has been implicated in a number of neurodegenerative diseases including Alzheimer’s disease and Parkinson’s disease. Nclk consists of a catalytic subunit, called cyclin dependent protein kinase 5 (Cdk5), and a 25 kDa regulatory subunit derived proteolytically from a 35 kDa neuronal-specific protein, called neuronal Cdk5 activator. Although Cdk5 protein exists ubiquitously, Nclk activity can only be found in brain because of the restricted expression of Cdk5 activator. This suggests that the activator is the crucial modulator for the Nclk activity. Thus our current researches focus on the identification of proteins that can interact with Cdk5 activators and can modulate the Cdk5 activity.
p21-activated protein kinase (Pak)
The small Rho GTPases family (including RhoA, Cdc42 and Rac1), which belongs to Ras small GTPase superfamily, is involved in a number of cellular processes including gene regulation, cell migration and cell division. Emerging evidences has shown that Rho GTPases also play a vital role in the regulation of neurite outgrowth and cell migration. One of the downstream effectors of Cdc42 and Rac1 is called p21-activated protein kinase (Pak), which contains a highly conserved N-terminal Cdc42/Rac1 binding domain and a C-terminal kinase domain. Six members of Pak kinase family have been identified and they are subdivided into 2 groups. Pak5, which belongs to the group II Pak family, is found to be highly expressed in brain and stimulates neurite outgrowth by downregulation of RhoA. Using the yeast-2 hybrid screening, we have identified several potential cellular partners of Pak5 and would like to further characterize the functional outcome of their interaction. Recently, we also found that group I Pak family member, Pak1, is overexpressed in liver cancer, which is one of the most common cancers worldwide and in Hong Kong. Thus, our researches also focus on the molecular mechanism by which Pak1 induces hepatocarcinogenesis.
Centrosome and cancer
Emerging evidence suggests that supernumerary centrosomes drive chromosomal instability and is linked to oncogenesis. Several viral oncoproteins, such as human papillomavirus (HPV) type 16 E6 and E7 and hepatitis B virus X protein (HBx), have been shown to transform cells by promoting centrosome abnormalities and formation of multipolar spindles. Thus it appears that induction of centrosome amplification may be a common strategy for viral-mediated oncogenesis. We have recently characterized a novel cellular centrosomal protein, which we named TAX1BP2 and have shown to play an important role in centrosome duplication. Thus we would like to understand further the molecular signaling of TAX1BP2 and how centrosome overduplication contributes to the development of cancer.
- Xu HT, Lai WL, Liu HF, Wong LL, Ng IO, Ching YP. “PAK4 Phosphorylates p53 at Serine 215 to Promote Liver Cancer Metastasis.” Cancer Res. (2016) Oct 1;76(19):5732-5742.
- Wang K, Yuen ST, Xu J, Lee SP, Yan HH, Shi ST, Siu HC, Deng S, Chu KM, Law S, Chan KH, Chan AS, Tsui WY, Ho SL, Chan AK, Man JL, Foglizzo V, Ng MK, Chan AS, Ching YP, Cheng GH, Xie T, Fernandez J, Li VS, Clevers H, Rejto PA, Mao M, Leung SY. Whole-genome sequencing and comprehensive molecular profiling identify new driver mutations in gastric cancer. Nature Genetics (2014);46(6):573-82
- Lai WL, Hung WH, *Ching YP. The tumor suppressor, TAX1BP2, is a novel substrate of ATM kinase. Oncogene (2014);33(45): 5303-9.
- Chan CP, Siu YT, Kok KH, *Ching YP, *Tang HMV, *Jin DY. Group I p21-activated kinases facilitate Tax-mediated transcriptional activation of the human T-cell leukemia virus type 1 long terminal repeats. Retrovirology (2013) Apr 26;10:47. doi: 10.1186/1742-4690-10-47
- Lai WL, Hung WY, Wong LL, Zhou Y, Leong VY, Lee JMF, Ng IOL, Jin DY, *Ching YP. The centrosomal protein Tax1 binding protein 2 is a novel tumour suppressor in hepatocellular carcinoma regulated by cyclin-dependent kinase 2. Hepatology (2012) 56(5): 1770-1781.
- Lee CW, Wong LL, Tse EY, Liu HF, Leong VY, Lee JM, Hardie DG, Ng IOL, *Ching YP. AMPK promotes p53 acetylation via phosphorylation and inactivation of SIRT1 in liver cancer cells. Cancer Research (2012) 72(17): 4394-4404.
- Mak GW, Chan ML, Leong VY, Lee JM, Yau TO, Ng IOL, *Ching YP. Overexpression of a novel activator of PAK4, the CDK5 kinase-associated protein CDK5RAP3, promotes hepatocellular carcinoma metastasis. Cancer Research (2011) 71(8): 2949-2958.
- *Ching YP, Leong VYL, Lee MF, Xu HT, Jin DY, *Ng IOL. Pak1 is overexpressed in hepatocellular carcinoma and enhances cancer metastasis involving JNK activation and paxillin phosphorylation. Cancer Research (2007) 67:3601-3608.
- Ching YP, Chan SF, Jeang KT, Jin DY. Retroviral oncoprotein Tax targets coiled-coil centrosomal protein TAX1BP2 to induce centrosome overduplication. Nature Cell Biology (2006) 8: 717-724.
- *Ching YP, Leong VYL, Wong CM, *Kung HF. Identification of an autoinhibitory domain of p21-activated protein kinase 5. J Biol Chem (2003) 278(36): 33621-33624.
- RGC GRF (2016-2018) “Functional characterization of the roles of Polo-like kinase 4, Plk4 in hepatocarcinogenesis”
- HMRF Full Grant (2015-2017) “A study of the role of CDK5RAP3 in neuronal cell differentiation”
- RGC GRF (2015-2018) “Functional characterization of the roles of NIMA-related kinase, Nek2 in liver cancer development and metastasis”
- Faculty Outstanding Research Output Award, The University of Hong Kong (2015) –Co-author
- Faculty Outstanding Research Output Award, The University of Hong Kong (2007)
- National Natural Science Foundation of China (NSFC) Young Scholar Award (2006-2007)
- Health and Medical Research Fund, Member of Grant Review Board (2013-present)
- Anatomy and Physiology, Academic Editor
- PLoS One, Academic Editor
- World Journal of Clinical Oncology, Academic Editor
- World Journal of Hepatology, Academic Editor
- Mr. Vincent Chan (MPhil student)
- Mr. Wallace Chan (RA)
- Mr Dennis Hu (PhD student)
- Dr. Sheila Lee (PDF)
- Miss Tiffany Tang (PhD student)
- SF Yeung (PhD student)
- Ms. Yuan Zhou (Technician)
- Ms. Ailis Zou (RA)