3-phosphoinositides

Dowex 1-X4 1.0 0.70 Strongly basic anion exchanger with S-DVB matrix for separation of organic acids, nucleotides, phosphoinositides, and other anions. Molecular weight exclusion is <1400. 

Akt is activated by binding of plasma membrane phospholipids downstream of insulin receptors, growth and survival factor receptors in a phosphoinositide 3-kinases dependent manner. In humans, there are three genes in the Akt family Aktl, Akt2 and Akt3. Their respective fimctions are still under investigation. 

Rhee SG, Bae YS (1997) Regulation of phosphoinositide-specific phospholipase Isozymes. J Biol Chem 272 15045-15048... 

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... 

Phospholipid Kinases. Figure 1 Major phosphoinositides pathways in mammalian cells. 

Phospholipid Kinases. Figure 2 Classification of phosphoinositide 3-kinases. 

Pleckstrin homology domain (PH-domain) was first identified at the amino and carboxyl termini of a haematopoietic protein called pleckstrin. PH-domain, a protein region of approximately 120 amino acids, by binding to phosphatidylinositol lipids of the biological membranes induces the translocation of the PH-domain containing protein to membrane compartment. Various PH-domains possess specificities for phosphoinositides phosphorylated at different sites within the inositol ring. 

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... 

PH Pleckstrin homology domain Binding to membrane phospholipids, such as phosphoinositides... 

The current understanding on activation of Tec kinases fits into a two-step model. In the first step an intramolecular interaction between the SH3 domain and aproline-rich region in the TH domain is disrupted by binding ofthe PH domain to phosphoinositides, G protein subunits, or the FERM domain of Fak. These interactions lead to conformational changes of Tec and translocation to the cytoplasmic membrane where, in a second step, Src kinases phosphorylate a conserved tyrosine residue in the catalytic domain thereby increasing Tec kinase activity. Autophosphorylation of a tyrosine residue in the SH3 domain further prevents the inhibitory intramolecular interaction resulting in a robust Tec kinase activation. 

Yang L, Williams DE, Kim J, Demirjian L, Qasimi R 53 Ruschmann J, Cao LP, Ma K, Chung SW, Duronio V, Andersen RJ, Krystal G, Mui AL Small-molecule agonists of SHIPl inhibit the phosphoinositide 3-kinase pathway in hematopoietic cells. Blood 2007 110 1942-1949. 

A bit further in the transduction cascade, the U.V. activation of caged IP3 electroporated in protoplasts triggered a peak of [Ca " ] and a full PAL activation. All these results point to the involvement, in response to pectic signals, of a phosphoinositide transduction pathway similar to the one existing in animal cells. 

Chemokine Signaling in T-Lymphocyte Migration The Role of Phosphoinositide 3-kinase... 

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