The PIKK Family of Protein Kinases
- Abstract:
- In the mid-1990s, a series of cloning papers announced the arrival of the phosphatidylinositol 3-kinase (PI3K)-related protein kinase (PIKK) family of proteins. These reports and subsequent studies revealed two defining features of this protein family. First, all known members are very large, being between 280 and 470 kDa in size. Second, despite being protein serine/threonine kinases, the kinase domains of PIKK family members are markedly different from those of other protein serine/threonine or tyrosine kinases and, instead, are more related in sequence (≈20 to 25% identity) to the kinase domain of the PI3K family of phospholipid kinases. Members of the PI3K family play diverse roles in intra-cellular signaling triggered by mitogenic and other stimuli through phosphorylating the inositol ring of phosphatidy-linositol derivatives, thus generating second messengers for downstream effector pathways. Nevertheless, the available evidence indicates that PIKK family proteins have specificity toward proteins rather than lipid targets. Although the primary specificities of the PIKK and PI3K families therefore appear to be different, it is likely that they bring about catalysis by very similar mechanisms. Over the past few years, it has become clear that members of the PIKK family exist in all eukaryotes studied, although none has so far been found in prokaryotes. Six human PIKK family members have been identified to date, and genome scanning suggests that this number is unlikely to increase. This chapter provides an overview of the PIKK family with particular emphasis on the human proteins.