Title: PKC signalling in cell proliferation and cancer
Funder: The Francis Crick Institute

Abstract: My laboratory is interested in the way in which control hierarchies operate under normal and pathological circumstances to determine the behaviour of cells, in particular the regulators that control proliferative and organizational properties of cells and their aberrant engagement in cancer. Specific nodes within these control hierarchies offer themselves as potential drug targets, particularly where they become actively hard wired into an essential process or by default become part of an emergent requirement due to the cancer-associated somatic loss of other cellular functions. Much of our work continues to be concentrated on AGC protein kinases with the PKC superfamily being the centre of focus. In this domain we have three main areas of activity that are concerned with (i) the role and mechanisms of action of PKC in failsafe pathways that become engaged in certain transformed cells and (in)validation of this kinase as a drug target, (ii) the action and intervention in atypical PKC (aPKC) with a particular interest in the (mutant) Ras connection, and (iii) the actions of the PKN sub-family of PKC protein kinases (collaboration with Dr Angus Cameron QMUL). In addition to this we are extrapolating our PKC findings and insights into aspects of kinase function, relating to Akt/PKB properties (collaboration Prof. Banafshe Larijani, Bilbao) and also in addressing the drugability of an established oncology target (AZ collaboration). We are unravelling the underlying mechanisms in a series of failsafe controls that operate in the cell cycle and are dependent on PKC. These include delays/checkpoints that we have published on (the abscission checkpoint and a Metaphase/Anaphase delay) as well as other cell cycle properties that come under PKC control apparently exclusively in a subset of transformed cells. The PKC driven molecular events that operate to effect these processes and their conditional engagement represents the substantial element of our work in this area. Most recently we have defined a non-canonical pathway involved in the activation of PKC in M-phase. In parallel we have developed a novel approach to identifying PKC (and other kinase) substrates, which is starting to yield new insights into downstream effectors. What the long-term consequences are of blockade of PKC in a context where there is apparent reliance on its action is a critical question also being addressed (collaboration GSK). In the aPKC area, we are interested in the relationship between the polarizing effect of this kinase and its associated partner proteins (Par3, Par6), and the pro-proliferative effect of this kinase, particularly in the context of Ras mutations. This is opening up a series of different aspects of aPKC action relating to targets, scaffolds and higher order complexes. With our long-standing collaborators, CRT, we have late stage inhibitors of aPKC in development. The PKN subfamily of protein kinases have been the poor cousins of the PKC superfamily. We have recently published the full repertoire of knock-outs of this family identifying PKN2 as an essential gene in the mouse with PKN1 and PKN3 serving no apparently essential role. We are exploiting the models we have created to address specific functions of these kinases as well as assessing more generally their roles in transformation processes.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS