Heung-Chin Cheng
Enzymology of protein kinases and phosphatases involved in cancer and neurodegeneration
The main focus of our group is enzymology of protein kinases and phosphatases involved in cancer and neurodegeneration. The protein kinases under investigation include Src-family tyrosine kinases, the Csk-homologous kinase (CHK), PTEN-induced kinase-1 (PINK1) and leucine-repeat-rich kinase 2 (LRRK2). For the phosphatases, we focus on the phospholipid and protein phosphatase PTEN. The ongoing projects are listed below.
Theme I: The roles of Src-family kinases (SFKs) and CHK in infection, cancer and neurodegenerative diseases
Src-family kinases (SFKs) are multi-domain protein kinases involved in a wide spectrum of cellular functions. Aberrant activation of SFKs contributes to the onset and progression of cancer and mediates the actions of several pathogens in host cells. SFK kinase activity is regulated by intramolecular interactions, and phosphorylation of tyrosines in the kinase domain and the C-terminal tail.
Autophosphorylation of a consensus residue in the kinase domain stabilizes the enzyme in the active conformation. Phosphorylation of a consensus residue in the C-terminal tail by the upstream kinases CSK and CHK leads to inactivation. Our group has been investigating the signaling specificity and regulation of SFKs and their upstream inhibitors CSK and CHK for many years. Our current focuses are:
- determination of the structure of CHK
- defining the structural basis of inhibition of SFKs by CHK
- deciphering the roles and mechanism of aberrant activation of SFKs in cancer, neurodegenerative diseases (in particular prion disease) and AIDS pathogenesis
In addition, we have initiated the development of chemosensor substrate peptides of SFKs for high throughput screening of specific SFKs inhibitors in vitro and in vivo.
Theme 2: Protein kinases involved in the pathogenesis of Parkinson’s disease
Parkinson’s disease (PD) is the most common human neurodegenerative movement disorder. The movement disorder is due to progressive preferential loss of dopaminergic neurons in the region of the mid-brain called the substantia nigra. However, the cause of premature death of dopaminergic neurons in PD is poorly understood. The PD-causative gene PINK1 was discovered in 2004. PINK1 encodes the mitochondrial protein kinase PTEN-induced kinase 1.
PINK1 is neuroprotective – it prevents premature death of neurons. It has been hypothesized that PD-associated mutations in PINK1 abolish the kinase activity of its protein product and consequently induce PD. How might PINK1 exert its neuroprotective function? Presumably, as a protein kinase, by phosphorylating specific proteins in the mitochondria. In this project, we aim to identify the physiological substrates of PINK1 in mitochondria and study how they mediate the neuroprotective functions of PINK1.
Theme 3: Structure and function of the tumour suppressor PTEN
Tumour suppressors promote cell death and suppress cell growth in body tissues. Mutations that abolish the activity if tumour suppressors contribute to the formation of many forms of cancer. Since joining the University of Melbourne, I have extended my research interest to members of this important group of proteins, in particular the Csk-family protein kinases and the phosphatase PTEN, a novel phospholipid and protein phosphatase.
Loss of PTEN function is associated with the development of more than 50% of human cancers. Exactly how PTEN functions in normal cells and how loss of PTEN function contributes to cancers is poorly understood. Our studies of PTEN's regulatory and catalytic properties are designed to answer these important questions. Specifically, we are studying how PTEN subcellular localisation and activity are regulated by tyrosine kinases and serine/threonine kinases.
Selected recent publications
- Chong YP, Chan AS, Chan KC, Williamson NA, Lerner EC, Smithgall TE, Bjorge JD, Fujita DJ, Purcell AW, Scholz G, Mulhern TD, Cheng H-C. (2006) ‘C-terminal Src kinase-homologous kinase (CHK), a unique inhibitor inactivating multiple active conformations of Src family tyrosine kinases’. J Biol Chem, 281, 32988-32999.
- Yi X, Yeong J, Chia C, Gajewski JE, Lio DSS, Mulhern TD, Zhu HJ, Nandurkar H, Cheng H-C. (2007) ‘PTEN catalysis of phospholipid dephosphorylation reaction follows a two-step mechanism in which the conserved aspartate-92 does not function as the general acid – Mechanistic analysis of a familial Cowden disease-associated PTEN mutation’. Cell Signalling 19, 1434-1445.
- Zhu S, Bjorge JD, Cheng H-C, Fujita DJ. (2008) ‘Decreased CHK protein levels are associated with Src activation in colon cancer cells’. Oncogene, 27, 2027-2034.
- Mills RD, Sim CH, Mok SS, Mulhern TD, Culvenor JG, Cheng H-C. (2008) ‘Biochemical basis of the neuroprotective mechanism of PTEN-induced kinase-1 (PINK1)’. J Neurochem, 105, 18-33.
Lab personnel
HeadAssociate Professor Heung-Chin ChengResearch staffDr Tim Johnson (Postdoctoral research associate, with Dr Janetta Culvenor) Graduate studentsKhai-Chew Chan Visiting graduate studentsJessica Chan (Menzies Institute, University of Tasmania) Honours studentLynn Tran |