PtdIns

Family of enzymes phosphorylating phosphatidylinositol (Ptdlns), PtdIns(4)phosphate, and PtdIns(4,5)phosphate in the 3-position. The Ptdlns(3 phospholipids are second messengers in processes like cell growth, cytoskeletal rearrangement, and vesicular transport. PI 3-kinases are heterodimers composed of a catalytic and a regulatory subunit. The enzymes are activated by insulin, many growth factors, and by a variety of cytokines. Their activity can be inhibited by wortmannin and LY294002. 

P2 is generated from PtdIns(4)P by the enzymatic activity of phosphatidylinositol 4-phosphate 5-kinase (PDP5K) (Fig. 1). Additional pathways are likely to be discovered. 

All class I PI3Ks are heterodimeric enzymes composed of a 110 kDa catalytic subunit (with the isoforms pi 10 a,(3,5 or y) that associates with a regulatory subunit. Although the class I PI3Ks are capable of phosphorylating Ptdlns, PtdIns(4)P and PtdIns(4,5)P2 in vitro, it appears that they only use PtdIns(4,5)P2 as a substrate in vivo. Receptor-induced formation of Ptdlns... 

Domin J, Harper L, Aubyn D, et al. The class II phosphoinositide 3-kinase PI3K-C2beta regulates cell migration by a PtdIns(3)P dependent mechanism. J Cell Physiol 2005 205(3) 452 162. 

Cote JF, Motoyama AB, Bush JA, Vuori K. A novel and evolutionarily conserved PtdIns(3,4,5)P3-binding domain is necessary for DOCK180 signalling. Nat Cell Biol 2005 7(8) 797-807. 

Adapted from [3]. Ptdlns, phosphatidylinositol PtdIns(4,5)P2, phosphatidylinositol-4,5-insphosphate PtdCho, phosphatidylcholine PtdEtn, phosphatidylethanolamine PtdSer, phosphatidylserine. 

The Chilton Conference nomenclature for inositol lipids is used throughout this chapter, e.g. PI, PI4P, PI(4,5)P2 for phosphatidylinositol, phosphatidylinositol 4-phosphate and phosphatidylinositol 4,5-bisphosphate respectively. Note that the IUB-recommended nomenclature for these lipids is Ptdlns, PtdIns4P and PtdIns(4,5)P2 (see Ch. 3). 

The relatively small pool of the precursor for Ins(l,4,5)P3, the phospholipid PtdIns(4,5)P2, is synthesized from the larger reservoir of phosphatidylinositol (Ptdlns) and, therefore, the supply of PtdIns(4,5)P2... 

Figure 1. Control of mitochondrial biogenesis by the nuclear genome. Most mitochondrial proteins, including cytochrome c, are nuclear gene products which are subsequently imported into mitochondria. Similarly, most enzymes involved in synthesis of mitochondrial phosphoplipids are encoded in the nuclear genome. Being located in the endoplasmatic reticulum, they synthesize phosphatidylcholine (PtdCho), phosphatidylserine (PtdSer), phosphatidylglycerol (PG) and phosphatidylinositol (Ptdins). The phospholipids are transferred to the outer membrane. The imported lipids then move into the inner membrane at contact sites. Mitochondria then diversify phospholipids. They decarboxylate phosphatidylserine to phosphatidylethanolamine (PtdEtN), but the main reaction is the conversion of imported phosphatidylglycerol to cardiolipin (CL). Cardiolipins localize mainly in the outer leaflet of the inner membrane.

SHIPl (hereafter SHIP) was identified in the early 1990s as a 145 kDa intracellular protein that is tyrosine phosphorylated upon the stimulation of hemeatopoietic cells via B and T-cell receptor, and by multiple cytokines (Damen et al, 1996, Lioubin et al. 1996). Molecular cloning of cDNA for SHP revealed that the molecule consists of an N terminal SH2 domain, a highly conserved, centrally located motif having Ptdins 5-phosphatase activity, two NPXY sequmces, which are phosphorylated on Tyr upon various stimuli and a proline-rich C terminus (Figure 2). SHIP hydrolyses PtdIns(3,4,5)/ 3, and inositol 1,3,4,5-tetrakisphosphate both in vitro and in vivo, thus belongs to the type n 5-phosphatases, charactaized also by their... 

At high concentration of antigen and at an immature developmental stage of B cells BCR cross-linking results in apoptosis (Norvell et al., 1995). In many cells SHIP mediated degradation of Ptdins polyphosphates promotes... 

Immortalized embryonic fibroblasts from PTEN-/- mice were shown to have elevated PtdIns(3,4,5)P3 level, constitutively elevated PKB/AKT activity and a decreased sensitivity to cell death in response to apoptotic stimuli (Stambolic et al, 1998). Homozygotic mutation of PTEN induced... 

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