Molecular Classification of PI3K

PI3K phosphorylates the D-3 position of inositol phospholipids. Three different classes can be distinguished, based on sequence homology and in vitro substrate specificity (Wymann and Pirola 1998). Class-I PI3Ks are heterodimers composed of a regulatory subunit and a PI3K catalytic subunit. They are involved in diverse cellular phenomena, such as control of growth (Leevers et al. 1996), regulation of cell cycle progression (Klippel et al. 1998; Gille and Downward 1999), DNA synthesis (Roche et al. 1994; Vanhaesebroeck et al. 1999), cell survival (Yao and Cooper 1995), actin rearrangements (Servant et al. 2000), and Ca2+ channel trafficking (Viard et al. 2004), by generating the phospholipid second messengers, phosphatidylinositol-3,4,5-trisphosphate [PtdIns(3,4,5)P3], and PtdIns(3,4)P2 in the plasma membrane of target cells.

Class-II PI3Ks are structurally distinct from the class I PI3Ks, and use only phosphatidylinositol and phosphatidylinositol-4-phosphate as substrates. They are constitutively associated with membrane structures (including plasma and intracel-lular membranes) and with nuclei. Several lines of evidence suggest a potential role for these enzymes in agonist-mediated signal transduction (Foster et al. 2003), migration of cancer cells (Maffucci et al. 2005), suppression of apoptotic cell death (Kang et al. 2005), exocytosis (Meunier et al. 2005), pattern formation (MacDougall et al. 2004), cytoskeletal organization (Katso et al. 2006), and insulin signaling (Falasca et al. 2007).

Class-III PI3Ks use only phosphatidylinositol as a substrate, producing PtdIns3P. The prototype for this enzyme, Vps34p, was first identified in Saccharo-myces cerevisiae, where it is required for delivery of soluble proteins to the vacuole (Herman et al. 1992; Schu et al. 1993). Subsequently, a human homolog was identified, and meanwhile Vps34p-related PI3Ks are known to exist in a wide range of eukaryotes, including Dictyostelium (Zhou et al. 1995) and Drosophila (Linassier et al. 1997), and it is this isoform that is found in plants too (Hong and Verma 1994; Welters et al. 1994; Molendijk and Irvine 1998). Since plants lack the class-I and -II PI3Ks, differences between plant and animal PI3K signaling can be expected.

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