3-phosphoinositide phosphatase

Begley M.J., Taylor G.S., Brock M.A., Ghosh P., Woods V.L. Jr, Dixon J.E. Molecular basis for substrate recognition by MTMR2, a myotubularin family phosphoinositide phosphatase. Proc. Natl Acad. Sci. USA 2006, 103, 927-932. 

Shisheva A. Regulating Glut4 vesicle dynamics by phosphoinositide kinases and phosphoinositide phosphatases. Front Biosci. 2003 8 s945-946. 

Tronchere, H., Buj-Bello, A., Mandel, J.L., and Payrastre, B., 2003, Implication of phosphoinositide phosphatases in genetic diseases The case of myotubularin. Cell Mol. Life Sci. 60 2084-2099. 

Williams, M.E., Torabinejad, J., Cohick, E., Parker, K., Drake, E.J., Thompson, J.E., Hortter, M., Dewald, D.B., 2005, Mutations in the Arabidopsis phosphoinositide phosphatase gene SAC9 lead to over accumulation of PtdIns(4,5)P2 and constitutive expression of the stress-response pathway. Plant Physiol. 138 686-700. 

Zhong, R., Burk, D.H., Naim, C.J., Wood-Jones, A., Morrison, W.H. and Ye, Z-H., 2005, Mutation of SAC1, an Arabidopsis SAC domain phosphoinositide phosphatase, causes alterations in cell morphogenesis, cell wall synthesis, and actin organization. Plant Cell 17 1449-1466. 

Maehama, T., Taylor, G.S., and Dixon, J.E., 2001, PTEN and myotubularin Novel phosphoinositide phosphatases. Annu. Rev. Biochem. 70 247-279. 

Begley MJ, Taylor GS, Kim SA et al (2003) Crystal structure of a phosphoinositide phosphatase, MTMR2 insights into myotubular myopathy and Charcot-Marie-Tooth syndrome. Mol Cell 12 1391-1402... 

All phosphoinositides are found in the cytosolic half of the lipid bilayer of the plasma or intracellular compartment membranes (left part). The different kinases acting on phosphoinositides in mammalian cells are shown in solid lines and the phosphoinositide 3-kinases, in bold. The phosphoinositides counterpart pathways catalysed by known phosphatases are represented by dashed lines. The best known phosphatases are PTEN (Phosphatase and tensin homolog deleted on chromosome 10) and SHIP (SH2 domain-containing inositol 5-phosphatase). 

Cellular phosphoinositide concentrations are under tight control by phospholipid kinases and phosphatases. Phospholipid kinases preferentially phosphorylate distinct positions of the inositol ring and hence are subdivided into phosphoinositide 3-kinases (PI3Ks), phosphoinositide 4-kinases (Pl4Ks), and phosphoinositide 5-kinases (PI5Ks) that phosphorylate Pis on position 3, 4 and 5, respectively. In a canonical pathway, Ptdlns... 

Transduction mechanism Inhibition of adenylyl cyclase stimulation of tyrosine phosphatase activity stimulation of MAP kinase activity activation of ERK inhibition of Ca2+ channel activation stimulation of Na+/H+ exchanger stimulation of AM PA/kainate glutamate channels Inhibition of forskol in-stimulated adenylyl cyclase activation of phos-phoinositide metabolism stimulation of tyrosine phosphatase activity inhibition of Ca2+ channel activation activation of K+ channel inhibition of AM PA/ kainate glutamate channels inhibition of MAP kinase activity inhibition of ERK stimulation of SHP-1 and SHP-2 Inhibition of adenylyl cyclase stimulation of phosphoinositide metabolism stimulation of tyrosine phosphatase activation of K+ channel inhibi-tion/stimulation of MAP kinase activity induction of p53 and Bax Inhibition of adenylyl cyclase stimulation of MAP kinase stimulation of p38 activation of tyrosine phosphatase stimulation of K+ channels and phospholipase A2 Inhibition of adenylyl cyclase activation/ inhibition of phosphoinositide metabolism inhibition of Ca2+ influx activation of K+ channels inhibition of MAP kinase stimulation of tyrosine phosphatase... 

Other enzymes present in myelin include those involved in phosphoinositide metabolism phosphatidylinositol kinase, diphosphoinositide kinase, the corresponding phosphatases and diglyceride kinases. These are of interest because of the high concentration of polyphosphoinositides of myelin and the rapid turnover of their phosphate groups. This area of research has expanded towards characterization of signal transduction system(s), with evidence of G proteins and phospholipases C and D in myelin. 

The inositol polyphosphate 5-phosphatases belong to a family of enzymes that terminate the signals generated by inositol lipid kinases and PLC. To date, two major types of 5-phosphatase have been identified, both of which share a common 5-phosphatase domain of approximately 300 amino acids, with several highly conserved motifs. Type-I enzymes are 43-65 kDa and preferentially hydrolyze 1(1,4,5)P3 and 1(1,3,4,5)P4, with the attendant formation of I(1,4)P2 and 1(1,3,4)P3, but have little or no activity towards membrane-bound phosphoinositides. The pro-totypic form of a type-15-phosphatase is a 43 kDa protein that is post-translationally modified by farnesylation of the carboxyl terminus CAAX motif this modification juxtaposes the enzyme with the membrane. Type-II enzymes are larger (75-160 kDa) and will hydrolyze both water-soluble inositol phosphates and lipids that... 

The ability of 3-phosphoinositides to stimulate cell proliferation/survival via activation of Akt is countered by the 3-phosphatase PTEN, which hydrolyzes PI(3,4)P2 and PI(3,4,5)P3. A link between PTEN activity and 3-phosphoinositide content in cells is evident from the observations that (a) overexpression of PTEN results in a dramatic reduction in the cellular content of these lipids, and (b) 3-phosphoinositide concentrations are greatly elevated in mammalian PTEN-null cell lines [28]. Cells in which PTEN activity is reduced have increased tumori-genic properties, since Akt inhibits apoptosis and promotes cell survival. Conversely, PTEN activity programs the fate of the cell toward apoptosis. Mutations of PTEN have been shown to occur in a wide range of tumor types, but with a particularly high frequency in glioblastomas. 

Gupta, N., Scharenberg, A.M., Emman, D.A., Cantley, L.C., Kinet, J-P., and Long, E.O., 1999, The SH2 domain containing inositol 5 -phosphatase (SHIP) recruits the p85 subunit of phosphoinositide 3-kinase during FoGRIIbl-mediated inhibition ofB cell receptor signaling. J. Biol. Chem. 274 7489-7494. 

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