INOSITOL-1,4,5-TRISPHOSPHATE 3-KINASE

Shears, S.B. The pathway of myo-inositol 1,3,4-trisphosphate phosphorylation in liver. Identification of myo-inositol 1,3,4-trisphosphate 6-kinase, myo-inositol 1,3,4-trisphosphate 5-kinase, and myo-inositol 1,3,4,6-tetrakisphosphate 5-kinase. J. Biol. Chem., 264, 19879-19886 (1989)... 

Somlyo AP, Somlyo AV 2000 Signal transduction by G-proteins, Rho-kinase and protein phosphatase to smooth muscle and non-muscle myosin II. J Physiol 522 177—185 Somlyo AP, Devine CE, Somlyo AV, N orth SR 1971 Sarcoplasmicreticulumand the temperature-dependent contraction of smooth muscle in calcium-free solutions. J Cell Biol 51 722—741 Somlyo AP, Walker JW, Goldman YE et al 1988 Inositol trisphosphate, calcium and muscle contraction. Philos Trans R Soc Lond B Biol Sci 320 399 114 Somlyo AP, Wu X, Walker LA, Somlyo AV 1999 Pharmacomechanical coupling the role of calcium, G-proteins, kinases and phosphatases. Rev Physiol Biochem Pharmacol 134 201-234... 

Francesconi, A. and Duvoisin, R. (2000) Opposing effects of protein kinase C and protein kinase A on metabotropic glutamate receptor signaling selective desensitization of the inositol trisphosphate/Ca2+ pathway by phosphorylation of the receptor-G protein-coupling domain. Proc. Natl. Acad. Sci. USA 97,6185-6190. 

Figure 12.5 Effector mechanism activation of a membrane-bound phospholipase. An example is activation of a membrane-bound phospholipase which hydrolyses phosphatidylinositol bisphosphate (PIP2) and results in the formation of the two messengers, inositol trisphosphate (IP3) and diacylglycerol (DAG). Messenger IP3 binds to a receptor on the endoplasmic reticulum that results in release of Ca ions into the cytosol. DAG, which remains within the membrane, activates protein kinase-C at the membrane surface. When the kinase leaves the membrane, it is unclear how it remains active or loss of activity is prevented, so that it can phosphorylate proteins in the cytosol or even the nucleus. An example is adrenaline binding to the a-receptor in the liver, in which Ca ions stimulate glycogenolysis.

Figure 21.6 One mechanism of activation of the cell cycle by a growth factor. Binding of growth factor to its receptor activates membrane-bound phospholipase-C. This hydrolyses phosphati-dylinositol bisphosphate in the membrane to produce the messengers, inositol trisphosphate (IP3) and diacylglycerol (DAG). IP3 results in release of Ca from an intracellular store. The increased Ca + ion concentration activates protein kinases including protein kinase-C (PK-C). DAG remains membrane-bound and also activates protein kinase-C (PK-C) which remains in the activated form as it travels through the cell where it phosphory-lates and activates transcription factors. This results in activation of genes that express enzymes involved in nucleotide synthesis, DNA polymerases and cyclins, which are all reguired for the cell cycle (See Chapter 20 for provision of nucleotides and cyclins for the cell cycle).

Major effector proteins for G-pro-tein-coupled receptors include adenylate cyclase (ATP intracellular messenger cAMP), phospholipase C (phos-phatidylinositol intracellular messengers inositol trisphosphate and di-acylglycerol), as well as ion channel proteins. Numerous cell functions are regulated by cellular cAMP concentration, because cAMP enhances activity of protein kinase A, which catalyzes the transfer of phosphate groups onto functional proteins. Elevation of cAMP levels inter alia leads to relaxation of smooth muscle tonus and enhanced contractility of cardiac muscle, as well as increased glycogenolysis and lipolysis (p. 

This enzyme [EC 2.7.1.133], also referred to as lo-myo-inositol-trisphosphate 6-kinase, catalyzes the reaction of ATP with iD-myo-inositol 1,3,4-trisphosphate to produce ADP and iD-myo-inositol 1,3,4,6-tetrakisphos-phate. 

Figure 14-3. Signaling through protein kinase C (PKC). Activated phospholipase C cleaves the inositol phospholipid PIP2 to form both soluble (IP3) and membrane-associated (DAG) second messengers. DAG recruits PKC to the membrane, where binding of calcium ions to PKC fully activates it. To accomplish this, IP3 promotes a transient increase of intracellular concentration by binding to a receptor on the endoplasmic reticulum, which opens a channel allowing release of stored calcium ions. PIP2, phosphatidylinositol 4,5-bisphosphate DAG, diacylglycerol PLC, phospholipase C IP3, inositol trisphosphate.

Biden, T.J. Comte, M. Cox, J.A. Wollheim, C.B. Calcium-calmodulin stimulates inositol 1,4,5-trisphosphate kinase activity from insulin-secreting RINm5F cells. J. Biol. Chem., 262, 9437-9440 (1987)... 

H. Mayr, G.W. Rat inositol 1,4,5-trisphosphate 3-kinase C is enzymatically specialized for basal cellular inositol trisphosphate phosphorylation and shuttles actively between nucleus and cytoplasm. J. Biol. Chem., 278, 19765-19776 (2003)... 

---