Edward Manser (right) obtained his BSc (Hons) (1982) in Biochemistry from Bristol University and his PhD (1986) at the National Institute for Medical Research, UK. After a post-doctoral period at the Institute of Neurology (London) he moved to IMCB in 1987. He holds an Associate Professor appointment in the GSK-IMCB Group and in IMB.

Thomas Leung (left) obtained his MSc (1978) in Clinical Biochemistry from the University of Newcastle, UK and his PhD (1981) in Biochemistry from London University. He was the Pewterer’s Fellow at the Institute of Neurology (London) before joining IMCB in 1986. He is an Associate Professor in the GSK-IMCB Group.

SCOPE OF ACTIVITIES: The GSK-IMCB Group was originally established as the Glaxo-IMCB Group, supported by the Glaxo (Singapore) Research Fund. This Fund was set up in 1989 to provide support for basic research into neural differentiation and degeneration at the IMCB for 15 years. Support has been renewed until 2009 and the term Glaxo replaced by GSK. For the last decade, the Group’s research has centred on signalling mechanisms that underlie processes of differentiation and migration common to most cell types, and which may require additional components in neuronal cells.

In executing its diverse activities, the cell undergoes a continual reorganization of its structural components. This reorganization is most evident when cells change shape in moving or differentiating. During differentiation, shape changes can be extreme, especially in neurons that put out numerous extensions when forming their neural signaling network. The formation mainly occurs after neurons migrate to their final destination, soon after dividing. In neurons as in all cell types, movement, differentiation and signalling events involve common contractile filaments. These filaments are regulated by protein kinases, which generally act through phosphorylating individual components, leading to their polymerization and subsequent formation of filaments. The kinases include PAK and MRCK, which were first discovered by the Group.

During brain development, both attractive and repulsive signals operate to ensure that extending axons find their appropriate destinations. When neurons are damaged though disease or trauma, the restoration of connectivity will require formation of new extensions (axons and their forerunners). However, scars arising at damage sites regenerate repulsive signals, such as the proteoglycan matrix that repels encroaching neuronal extensions. The latter repulsion can be overcome by using a small PAK fragment. For its varied activities, PAK is brought to different intracellular sites through its interaction with targeting partners, such as PIX and GIT. A newly discovered partner (and substrate) is the important cell division kinase Aurora-A. Another is the fragile X-lined mental retardation protein, FMRP. In the brain, FMRP and its own partners are responsible for bringing mRNA to sites where local protein synthesis is needed for continued signalling and receptivity. Another kinase previously shown to be required for axonal outgrowth is MRCK. We now find that MRCK regulates the myosin component of acto-myosin contractile filaments, whose rearward movement is needed for forward propulsion of the cell.

CONCLUSION: Clearly, PAK and MRCK regulate a multiplicity of cellular functions, and indeed their discovery marked a new phase in understanding signaling by Rho proteins. These kinases are brought to sites in the cell by specific protein partners - and this is the future focus of the group. The ability to disrupt kinase partnerships (i.e. kinase targeting) may provide an alternate means for treating degenerative disorders or trauma where neuronal connectivity is diminished. That kinases such as PAK5 are commonly over-expressed in cancers suggests that inhibitors of the non-conventional kinases might be of therapeutic use.