Introduction

The PKC family tree

Figure 1: The PKC family tree

As critical regulatory nodes, protein kinases are central to the normal and pathological behavior of cells.

Our interest is in a subset of kinases within this gene family (the PKC genes), in particular their roles in transformed behaviours, the potential for intervention and the broader lessons that we can apply.

The development, propagation and spread of cancer are sustained by altered properties and inappropriate actions of normal physiological processes hijacked through the acquisition of genetic changes. Typically this involves gain or loss of function of particular gene products present in all of us and acting in the normal setting to effect highly orchestrated programmes of tissue maintenance, growth and regeneration in line with preserving normal tissue size and function.

Among the most widely engaged gene products in these physiological and pathological events are a family of over 500 multifunctional regulators, the protein kinases. These are some of the most frequently mutated gene products in cancer and many of the new, targeted therapeutics now in use in cancer treatments are directed at members of this protein kinase family. Understanding the physiological and pathophysiological regulatory networks of these kinases provides important insight into the liabilities and opportunities for intervention. Among this regulatory gene super-family are the protein kinase C (PKC) family, comprising a group of four closely related branches of the AGC kinase class.

In the context of cancer pathophysiology, we are working to understand how particular members of this protein kinase family act to influence properties particular to cancer - specifically, deregulated growth, survival and migration/invasion. Developing detailed molecular definitions of these events and assessing how the normal, physiological requirements for these kinases compare to the abnormal pathological requirements, provides evidence on the mechanisms and progression of disease, as well as biomarkers indicative of kinase action and insights into the potential value of intervention. Where appropriate, we have moved from these models to initiate collaborative drug development programmes, exploiting these insights to bring new agents into the clinic.

Selected publications