Phosphatidylinositol phosphate-activated proteins

Fig. 9. Speculative scenario of nutrient y-linolenic acid (GLA)/linoleic acid (LA) modulation of nuclear transcription factor. Abbreviations 15-LOX, 15-lipoxygenase 15S-HETrE, 15S-hydroxyeicosatrienoic acid 13-HODE, 13-hydroxyoctadecadienoic PIP, phosphatidylinositol phosphate PKC, protein kinase C DAG, diacylglycerol MAPK, mitogen-activated protein kinase AP-1, activator protein 1.

The binding of the sperm to a receptor on the membrane of the oocyte either activates a membrane-bound phospholipase or releases a phospholipase into the oocyte. The phospholipase hydrolyses phosphatidylinositol bisphos-phate to produce the two intracellular signals, inositol tris-phosphate (IP3) and diacylglycerol within the ovum. As in other cells, the IP3 signal increases the level of cytosolic Ca + ions and the diacylglycerol (DAG) signal activates protein kinase C. 

As in the case of sstl, agonist binding to sst4 has and has not been shown to be sensitive to GTP and PTX similarly, inhibition of AC was and was not observed (Demchyshyn et al. 1993 Raynor et al. 1993a Kaupmann et al. 1994 Roosterman et al. 1997). In transfected cells, sst4 was functionally coupled, in a PTX-sensitive fashion, not only to inhibition of AC, but also to activation of arachidonate release and mitogen-activated protein kinase cascade (Bito et al. 1994 Shimizu et al. 1996). These effects were accompanied by the phosphorylation of 85-kDa cytosolic phospholipase A2 and were inhibited by the phosphatidylinositol-3-phosphate kinase inhibitor wortmannin. 

Fig. 11.13. Insulin receptor signaling. The insulin receptor is a dimer of two membrane-spanning a-(3 pairs. The tyrosine kinase domains are shown in blue, and arrows indicate auto-crossphosphorylation. The activated receptor binds IRS molecules (insulin receptor substrates) and phos-phorylates IRS at multiple sites, thereby forming binding sites for proteins with SH2 domains Grb2, phospholipase C"y(PLC"y), and PI 3-kinase. These proteins are associated with various phosphatidylinositol phosphates (all designated with PIP) in the plasma membrane.

Matsui, T., Yonemura, S., Tsuldta, S. and Tsukita, S. (1999). Activation of ERM proteins in vioo by Rho involves phosphatidylinositol -phosphate 5-kinase and not ROCK kinases. Curr. Biol. 9, 1259—1262. 

Gomez-Munoz, A., Kong, J.Y., Parhar, K., Wang, S.W., Gangoiti, R, Gonzalez, M., Eive-mark, S., Salh, B., Duronio, V., Steinbrecher, U.P. (2005) Ceramide-1-phosphate promotes cell survival through activation of the phosphatidylinositol 3-kinase/protein kinase B pathway. FEBS Lett. 579, 3744-3750. 

Figure 1. Simplified schematic of receptor-mediated signal transduction in neutrophils. Binding of ligand to the receptor activates a guanine-nucleotide-binding protein (G protein), which then stimulates phospholipase C. Phosphatidylinositol 4,5-bis-phosphate is cleaved to produce diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). DAG stimulates protein kinase C. IP3 causes the release of Ca from intracellular stores, which results in an increase in the cytosolic Ca concentration. This increase in Ca may stimulate protein kinase C, calmodulin-dependent protein kinases, and phospholipase A2. Protein phosphorylation events are thought to be important in stimulating degranulation and oxidant production. In addition, ionic fluxes occur across the plasma membrane. It is possible that phospholipase A2 and ionic channels may be governed by G protein interactions. ...

FIPhosphatidylinositol cycle. A = activator CMPPA = cytidine monophosphate phosphatidic acid DAG = diacylglycerol G = G protein Glu-6-P, glucose 6-phosphate IPj = inositol monophosphate IP2 = inositol biphosphate ... 

Fig. 3. A simplified illustration of BCR-ABL and SRC family kinase involvement in oncogenic signaling pathways. The inhibitory effect is indicated by the upside-down T s. ABL = Abelson tyrosine kinase BCR = breakpoint cluster region FAK = focal adhesion kinase Grb-2 = growth factor receptor-bound protein 2 HcK = hematopoietic cell kinase JNK = Jun amino-terminal kinase P = phosphate group PI3 K = phosphatidylinositol-3-kinase SFK = SRC family kinases StatS = signal transducer and activator of transcription 5. (Reprinted with permission from Ref (123)). 

Phospholipase C hydrolyzes the bond between glycerol and phosphate in phosphatidylinositol 4,5-bisphos-phate, releasing two products inositol 1,4,5-trisphos-phate (IP3), which is water-soluble, and diacylglycerol, which remains associated with the plasma membrane. IP3 triggers release of Ca2+ from the endoplasmic reticulum, and the combination of diacylglycerol and elevated cytosolic Ca2+ activates the enzyme protein kinase C. 

Phospholipase C, which initiates the release of phosphatidylinositol derivatives, also requires Ca2+ for activity. It is difficult to determine whether release of Ca2+ is a primary or secondary response. There are three isoenzyme types of phospholipase C-(3, y, and 8- and several sub forms of each with a variety of regulatory mechanisms.298 3"" For example, the y isoenzymes are activated by binding to the tyrosine kinase domain of receptors such as that for epidermal growth factor (see Fig. 11-13). In contrast, the (3 forms are often activated by inhibitory G proteins and also by G, which is specific for inositol phosphate release. 

Phosphorylated IRS-1 activates a second signaling pathway by interacting with an 85-kDa SH2-containing protein that is a subunit of phophatidylinositol 3-kinase.384 386 This activates the 110-kDa catalytic subunit of the 3-kinase, which catalyzes formation of phosphatidylinositol 3-phosphate as well as Ptdlns (3,4)P2 and Ptdlns (3,4,5)P3.387/387a These compounds, which remain within membranes, activate other branches of the signaling cascade, some of which may converge with those of the MAP kinase cascade. However, there appears to be specific activation of a ribosomal Ser/Thr kinase that, among other activities, phosphorylates ribosomal protein S6, a component of the small ribosomal subunit.388 It also phosphorylates some isoforms of protein kinase C and other enzymes. Ptdlns 3-kinase may also activate 6-phosphofructo-2-kinase (Fig. 11-2, step ti).384/388... 

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