Good, Jessie Ann Le; (1999) Regulation of atypical PKCs. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Protein phosphorylation plays an essential role in a diverse array of signalling cascades and regulates many cellular processes. Protein kinase Cs (PKCs) constitute one of the families of kinases involved in phosphorylating substrates on serine or threonine residues. These kinases were initially identified as being receptors for tumour promoters (phorbol esters) and the conditions required to activate different isoforms determine the subgroup classification of the 10 isoforms. Classical PKCs (α,β1, βII and γ) depend upon Ca2+ and lipids (DAG, PS- phospholipids.) Novel PKCs (δ, ϵ, η, μ and θ) are insensitive to Ca2+ but are activated by lipids, DAG and phospholipids. The atypical PKCs (ζ, i and λ) differ greatly. These proteins are insensitive to Ca2+ and phorbol ester binding. The lack of knowledge on the control of the atypical PKCs has made the role of the atypical PKCs more elusive. Nevertheless, PKC ζ has been implicated in cell growth and differentiation. Moreover, PKC ζ is thought to be involved in a plethora of signal transduction pathways, including the Ras and MEK/MAPK pathways. The related atypical PKC i may be involved in UV induced apoptosis and insulin signalling. The aims of this thesis are to define the control and biological role of the atypical PKCs - primarily focusing on PKC ζ. As one approach, the project attempted to create a knockout mouse. This would help define a biological end point and therefore permit elucidation of the inputs. This study led to the identification of a pseudogene and its origin is described. As a second approach to investigate PKC ζ control, various direct paths were followed - ranging from searching for potential binding proteins and cellular localisation, to analysis of activation by lipids and phosphorylation. These studies have provided evidence for the dynamic control of PKC ζ (and PKC i) through a kinase cascade involving the lipid kinase PI3-kinase, the lipid responsive PDK1 and finally phosphorylation of PKC ζ at a site defined as threonine 410. The operation of this pathway and its influence on PKC ζ autophosphorylation (in vivo) and activity (in vitro) are presented.

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