Phosphatidylinositol-3-kinases related kinases

The double edged sword effect of Cd ", namely apoptosis and cancer progression, is reflected in its opposing effects on p53. Cd " inhibits DNA base excision repair in p53-dependent and -independent manners [593], increases p53 phosphorylation as a prelude to apoptosis [594,595], and arrests cells in G1 and G2/M checkpoints via p53-dependent [510] and -independent [596] mechanisms. Cd " can affect p53 in two ways p53 is activated by phosphorylation via phosphatidylinositol-3-kinase related kinases [479] or Cd replaces zinc to maintain its mutated non-DNA binding form preventing apoptosis induction [597]. 

Of the different classes of non-protein kinases, the development of inhibitors of lipid kinases has received by far the most attention. A majority of this work centers on inhibitors of phosphatidylinositol kinases, which reflects the important role that phosphatidylinositols play as second messengers. In this section, we review inhibitors of PI3K and related kinases, as well as inhibitors of other phosphatidyl inositol kinases. We also discuss sphingosine kinase inhibitors and we end this section with a brief summary of inhibitors of other lipid kinases. 

Buckley, J.T. Properties of human erythrocyte phosphatidylinositol kinase and inhibition by adenosine, ADP and related compounds. Biochim. Biophys. Acta, 498, 1-9 (1977)... 

The family of heterotrimeric G proteins is involved in transmembrane signaling in the nervous system, with certain exceptions. The exceptions are instances of synaptic transmission mediated via receptors that contain intrinsic enzymatic activity, such as tyrosine kinase or guanylyl cyclase, or via receptors that form ion channels (see Ch. 10). Heterotrimeric G proteins were first identified, named and characterized by Alfred Gilman, Martin Rodbell and others close to 20 years ago. They consist of three distinct subunits, a, (3 and y. These proteins couple the activation of diverse types of plasmalemma receptor to a variety of intracellular processes. In fact, most types of neurotransmitter and peptide hormone receptor, as well as many cytokine and chemokine receptors, fall into a superfamily of structurally related molecules, termed G-protein-coupled receptors. These receptors are named for the role of G proteins in mediating the varied biological effects of the receptors (see Ch. 10). Consequently, numerous effector proteins are influenced by these heterotrimeric G proteins ion channels adenylyl cyclase phosphodiesterase (PDE) phosphoinositide-specific phospholipase C (PI-PLC), which catalyzes the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) and phospholipase A2 (PLA2), which catalyzes the hydrolysis of membrane phospholipids to yield arachidonic acid. In addition, these G proteins have been implicated in... 

Ataxia telangiectasia is an autosomal recessive disease characterized by neurologic, endocrine, and hepatic abnormalities, as well as a predisposition to malignancy (119). The defect has been traced to a gene on chromosome 11, the ATM gene that codes for a phosphatidylinositol 3-kinase-like protein which is related to the catalytic subunit of DNA-dependent protein kinase. This protein has a role in signal transduction, DNA repair, and control of the cell cycle (120). Affected patients have a defect in cell-mediated immunity. A decrease in semm IgA is seen in a majority of affected patients. IgG2 or total IgG and IgE levels may be decreased, with an increase in IgM. Patients are susceptible to chronic respiratory... 

M.D. Expression and characterization of the p85 subunit of the phosphatidylinositol 3-kinase complex and a related p85 p protein by using the baculovirus expression system. Biochem. J., 288, 395-405 (1992)... 

Velloso, L.A. Carvalho, C.R.O. Rojas, F.A. Folli, R Saad, M.J.A. Insulin signaling in heart involves insulin receptor substrates-1 and -2, activation of phosphatidylinositol 3-kinase and the JAK 2-growth related pathway. Cardiovasc. Res., 40, 96-102 (1998)... 

Cafferkey, R. Young, P.R. McLaughlin, M.M. Bergsma, D.J. Koltin, Y. Sathe, G.M. Faucette, L. Eng, W.K. Johnson, R.K. Livi, G.P. Dominant missense mutations in a novel yeast protein related to mammalian phosphatidylinositol 3-kinase and VPS34 abrogate rapamycin cytotoxicity. Mol. Cell. Biol., 13, 6012-6023 (1993)... 

Kang KW, Choi SH, Kim SG. 2002. Peroxynitrite activates NF-E2-related factor 2/ antioxidant response element through the pathway of phosphatidylinositol 3-kinase The role of nitric oxide synthase in rat glutathione S-transferase A2 induction. Nitric Oxide 7 244-253. 

Takahashi, K., Nakagawa, M., Young, S.G., and Yamanaka, S. (2005). Differential membrane localization of ERas and Rheb, two Ras-related proteins involved in the phosphatidylinositol 3-kinase/mTOR pathway. J Biol Chem 280 32768-32774. 

Kang, K.W., Lee, S.J., et al., Phosphatidylinositol 3-kinase regulates nuclear translocation of NF-E2-related factor 2 through actin rearrangement in response to oxidative stress. Mol. Pharmacol., 62, 1001-1010, 2002. 

Protein kinase C (PKC) may play a role in tonic tension. PKC refers to a family of related serine/threonine kinases, five of which are found in smooth muscle. PKC is activated by diacylglycerol, or DAG. DAG (and also IP3) is liberated from membranes by the action of phospholipase C (PLC) on phosphatidylinositol 4,5-bisphosphate, or by the action of phospholipase D (PLD) on phosphatidylcholine. A number of receptor-mediated events are transduced by activation of these lipases. Some agents that elicit tonic contraction (e.g., angiotensin II) activate PLD, thus producing DAG (but not IP3), which activates PKC with no effect on [Ca +]j. There are at least three sites on LC20 that can be phosphorylated by PKC, but it is not known which one, if any, of these is involved in the induction of contraction and latch. 

The number and breadth of reports of synthetic studies relating to phos-phatidylinositols and related structures has increased markedly as the following selection demonstrates. A series of unnatural phosphatidylinositols (41) with C2 to C18 fatty acids replacing the natural C20 fatty acid at the sn-2 position have been prepared and subjected to phosphorylation conditions with phos-phatidylinositol 3-kinase. The results show that phosphorylation can be achieved in molecules carrying small fatty acid side chains Cg shows reactivity comparable to that of the natural substrate. l-D-l-(sn-3-Phosphatidyl)-myo-inositol (42) has been prepared in excellent yield by the direct phosphatidylation of l-D-2,3,4,5,6-penta-0-benzyl-myo-inositol with sn-3-phosphatidic acid and subsequent deprotection (Scheme 6) The method has the advantage of producing products of unequivocal structure and stereochemical purity and being... 

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