*14.1. Kinases*

The kinase isoforms are divided into three major families: PI 4-kinases (PI4Ks), the PI 3-kinases (PI3Ks), and PIP (PIP) kinases (PIPKs) [127]. The nomenclature for these is a bit confusing, as some enzymes termed "PI-kinases" actually act primarily as PIP kinases. For example, Type I PI-3 kinases primarily use PI(4,5)P2 as their substrate to produce PI(3,4,5)P3, and there is little evidence for a substantial portion of cellular PI(3)P being formed by these enzymes. When the Type III PI-3 kinase, Vps34, was knocked out in mouse rod cells and phosphoinositide levels measured, the results suggested complete ablation of PI(3)P despite the presence of the Type I enzyme [22]. Several of these have been reported to be expressed in retina or RPE at the level of protein, mRNA or enzyme activity and most, if not all, are likely present at some level; however, as far as their functions, only the Type I and Type III PI-3 kinase have been studied using gene knockouts in the retina and RPE [22,49,57,128]. Global knockouts have been produced for the α, β, and γ isoforms of Type I PIP-kinases, which are the major source of PI(4,5)P2 in most cells [16]. Of these, the γ isoform seems to have the highest expression in the retina [129] and in other neurons [130,131] and leads to severe neuronal phenotypes and early postnatal mortality when knocked out [132]. Type II PIP-kinases have been observed in retina and are reported to be regulated by tyrosine phosphorylation [133]. The proteins encoded by the mouse genes, Pip4k2a, Pip4k2b, Pip4k2c, Pip5k1a, and Pip5k1c were all observed in a proteomic study of mouse retina [134].
