Beeton, Carolyn Ann; (2000) Functional differences of class 1a PI 3'-kinase heterodimers. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

This thesis describes a study of the class 1a phosphoinositide (PI) 3-kinase enzymes. PI 3-kinases generate lipids which have been implicated in receptor-stimulated signalling in mammalian cells and in a signalling complex which mediates protein trafficking in yeast. Whilst phosphoinositide 3-phosphate (PtdIns(3)P) is constitutively present in eukaryotic cells, PtdIns (3,4)P2 and PtdIns(3,4,5)P3 are almost absent from resting cells, but rise sharply following cell stimulation. These lipids have been implicated in a diverse range of cellular processes, ranging from mitogenesis and oncogenic transformation to insulin triggered changes in glucose transport. Given the central role of PI 3-kinases in such a variety of events, a study was undertaken to investigate regulation of this enzyme. Class 1a PI 3-kinases are 110- 120 kDa proteins that associate with adapter subunits containing Src homology-2 (SH2) domains, thereby linking the lipid kinase activity of PI 3-kinase to tyrosine kinase signalling pathways. Various adapter gene products and splice variants have been identified in recent years, and there are at least three genes encoding the catalytic subunit of the class 1a enzyme, but surprisingly little evidence has accumulated for different cellular roles of these isoforms. The studies described here define clear differences in the intrinsic activity of two of the catalytic isoforms of PI 3-kinase, p110α and p110β, and show that other cellular proteins can influence catalytic activity by binding specific domains of the adapter subunit. It is widely assumed that all signalling functions of PI 3-kinases are mediated by their lipid kinase activity. However, they also have a limited protein kinase activity, and the role of this is discussed. In addition, evidence is presented that the catalytic subunit influences enzyme recruitment to signalling complexes following cell stimulation.

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