Phosphatidylinositide Kinases

I. The phosphatidylinositide 3-kinase (PI 3-kinase) pathway, in particular, effects mediated through its effector protein kinase B (PKB, also termed Akt three isoforms) ... 

Figure 7.1 Major signaling pathways relevant to this chapter. Simplified schematic diagram of the major signaling pathways which impinge on mRNA translation I. The phosphatidylinositide 3-kinase (PI 3-kinase) pathway II/III. MAP kinases, especially the classical MAP kinase (ERK) pathway and the p38 MAP kinase pathway IV. The mammalian target of rapamycin (mTOR) pathway. Strictly, this diagram shows the rapamycin-sensitive events linked to mTORCl. Selected inhibitors and their sites of action are shown. A numberof components and cross-connections have been omitted for clarity.

Several metabohc pathways lead from phosphatidyl inositol to compounds with second messenger" character (review Liscovitch and Cantley, 1994 Divecha and Irvine, 1995). One main pathway, the formation of diacylglycerol and Ins(l,4,5)P3 from PtdIns(4,5)P2, has already been described in 6.4 and Fig. 6.3. Other compounds of regulatory importance can be formed by phosphorylation at the 3 position of the inositol part of Ptdins (Fig. 6.9). The reaction is catalyzed by a class of enzymes known as phosphatidylinositide 3-kinases (P13-kinases). The P13-kinases phosphorylate various phosphatidyl inositol compoimds at the 3 position. For example, PtdIns(3,4,5)P3, produced by 3 phosphorylation of Ptdlns(4,5)P2, has an important function as an intracellular messenger (see 6.6.2). 

Munnik, T., Irvine, R.F. and Musgrave, A., 1994, Rapid turnover of phosphatidylinositol 3-phosphate in the green alga Chlamydomonas eugametos signs of a phosphatidylinositide 3-kinase signaling pathway in lower plants Biochem. J. 298 269-273. 

Brunskill NJ, Stuart J, Tobin AB, Walls J, Nahorski S. Receptor-mediated endocytosis of albumin by kidney proximal tubule cells is regulated by phosphatidylinositide 3-kinase. J. Clin. Invest. 1998 101 2140-2150. 

ZHANG J, King WG, Dillon S, Hall A, FEIG L, RITTENHOUSE SE. Activation of platelet phosphatidylinositide 3-kinase requires the small OTP-binding protein Rho. JBiol Chem 268 22251-22254, 1993. 

W. Yu, J. Cassara, and P.F. Weller, Phosphatidylinositide 3-kinase localizes to cytoplasmic lipid bodies in human polymorphonuclear leukocytes and other myeloid-derived cells. Blood, 2000, 95, 1078-1085. 

Rgu re 14.23 Action of a lipid kinase in insulin signaling. Phosphorylated IRS-1 and IRS-2 activate the enzyme phosphatidylinositide 3-kinase, an enzyme that converts PIP into PIPj,... 

Phosphoinositol kinases Phosphatidylinositol kinases Phosphatidylinositide kinases... 

Class II hormones, which bind to cell surface receptors, generate a variety of intracellular signals. These include cAMP, cGMP, Ca +, phosphatidylinositides, and protein kinase cascades. 

PKC is a serine/threonine protein kinase comprised of at least 11 isozymic forms (Nishizuka 1995 Liu and Heckman 1998). These isozymic forms have been classified as atypical, classical, and novel. Classical PKCs (a, pi, pH, and y) are activated by Ca2+, DAG, phosphatidylserine (PS), and the tumor promoter phorbol 12-myristate 13-acetate (PMA). Novel PKCs (6, e, r, i, and 0) are activated by DAG, PS, and unsaturated fatty acids, while atypical PKCs (C, A, and 0 are insensitive to DAG but are activated by PS and phosphatidylinositides (reviewed in Liu and Heckman 1998 Newton and Johnson 1998 Nakanishi et al. 1993). PKCs have been implicated in a wide variety of cellular responses, including growth, differentiation, gene expression, angiogenesis, contractility, and vesicle trafficking (Nishizuka 1995). 

Fig. 8. Inteiconversions of phosphatidylinositides. PI, phosphatidylinositol PI-4-P, PI-4-phosphate PI-4.5-P2, PI-4,5-bisphosphate PI-3,4,5-P5, PI-3,4,5-trisphosphate PI 3K, PI-3-kinase PTSE, PI phosphate phosphatase PI 5K, PI 5 kinase PI 4K, PI 4 kinase.

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