Centre of Cell Signalling, Barts Cancer Institute, Queen Mary University of London, London, EC1M 6BQ, UK
The PI3K enzymes are heterodimeric molecules which consist of a catalytic p110 subunit, and a constitutively bound p85 regulatory unit of which there are five isoforms encoded by three genes (PIK3R1, PIK3R2 and PIK3R3) (Vanhaesebroeck and Waterfield, 1999; Geering et al., 2007).
The regulatory subunit has a dual function of recruiting the p110 catalytic subunit to an activated upstream tyrosine kinase receptor, and inhibiting catalytic activity in the absence of this stimulatory interaction (Yu et al., 1998). Unlike p110alpha, p110delta does not phoshorylate its associated p85 regulatory subunit and instead auto-phosphorylates (Vanhaesebroeck et al., 1997; Vanhaesebroeck et al., 1999a).
A transcription factor binding cluster located immediately upstream of the untranslated exon -2a in the human gene, has been identified and found to have enhanced promotor activity in leukocytes. This promoter region may therefore facilitate the enhanced expression of p110delta in leukocytes (Kok et al., 2009).
Roles of p110delta in immune function. The role of p110delta in vivo has been studied in a p110delta null mouse (Clayton et al., 2002; Jou et al., 2002) and in a p110delta kinase-dead mouse known as p110deltaD910A/D910A (Okkenhaug et al., 2002). Phenotypic analysis of the p110deltaD910A/D910A mouse revealed an important role for p110delta in immunity; the mice have notable defects in their T and B cell responses, as well as several other immunological abnormalities (Okkenhaug et al., 2002). In vitro and ex vivo studies suggest that p110delta is the predominant PI3K class IA isoform regulating the phenotype and responses of many leukocyte cell types (Vanhaesebroeck et al., 1999b; Puri et al., 2004; Papakonstanti et al., 2008). In mast cells derived from the p110delta kinase-dead mice, ninety percent of the total PI3K lipid kinase activity was dependent on p110delta (Ali et al., 2004). p110delta has been found to be a key player in the induction of amongst other things, proliferation, chemotaxis, and cytokine/chemokine release in response to both physiological stimuli and pathological stimuli, in many leukocytes (Okkenhaug and Vanhaesebroeck, 2003; Dos Santos et al., 2007; Papakonstanti et al., 2008; Dil et al., 2009; Low et al., 2010).
Emily Burns ; Bart Vanhaesebroeck
PIK3CD (phosphoinositide-3-kinase, catalytic, delta polypeptide)
Atlas Genet Cytogenet Oncol Haematol. 2011-02-01
Online version: http://atlasgeneticsoncology.org/gene/46261/pik3cd