Intracellular concentrations of inositol, glycerophosphoinositol and inositol pentakisphosphate increase during haemopoietic cell differentiation

Mountford, Joanne C.; Bunce, Christopher M.; French, Philip J.; Michell, Robert H.; Brown, Geoffrey

doi:10.1016/0167-4889(94)90030-2

Cited by 35 publications

(21 citation statements)

References 37 publications

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“…IP 5 is known to increase during hematopoietic cell differentiation and accumulates at higher concentrations than IP 3 and IP 4 (20). These observations raised the possibility that IP 5 is a physiological ligand and activates Btk function in vivo, although the activation mechanism remains unknown.…”

Section: Discussionmentioning

confidence: 88%

Mutation of the Pleckstrin Homology Domain of Bruton's Tyrosine Kinase in Immunodeficiency Impaired Inositol 1,3,4,5-Tetrakisphosphate Binding Capacity

Fukuda

Kojima

Kabayama

et al. 1996

Journal of Biological Chemistry

204

177

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Bruton's tyrosine kinase (Btk) 1 is a member of the Btk/Tec/ Itk subfamily of cytoplasmic tyrosine kinases (1-4). Btk contains a pleckstrin homology (PH) domain and adjacent Tec homology (TH) domain (5), in addition to the Src homology domain 3 (SH3), SH2, and SH1 (catalytic domain; Fig. 1A). Btk is crucial for B cell development and proliferation at the transition between the pre-B cell stage and later B cell stages. Mutations in the Btk gene cause a decrease in the number of mature B cells, resulting in human X-linked agammaglobulinemia (XLA) (1, 2) and murine X-linked immunodeficiency (Xid) (3, 4). Mutations in XLA patients, including missense and nonsense mutations, insertions, and deletions, have been found to be scattered all along the Btk gene (6). The mutations in the PH domain are important in determining the role of PH domain in signal transduction, because thus far Btk is the only protein in which mutations in the PH domain have been found to cause a disease. The PH domain is a divergent protein module of approximately 100 amino acids found in many proteins involved in signal transduction, and there is evidence that it is involved in protein-protein or protein-phospholipids interactions (for reviews, see Refs. 7 and 8). Although the PH domain of Btk binds the ␤␥ subunits of heterotrimeric G proteins (9, 10) and several protein kinase C (PKC) isoforms (11), the effect of the XLA and Xid mutations in the PH domain on this binding has not been fully elucidated.Very recently, we showed that the PH domain of Gap1 m , a member of a family of Ras GTPase-activating proteins, binds inositol 1,3,4,5-tetrakisphosphate (IP 4 ), inositol 1,3,4,5,6-pentakisphosphate (IP 5 ), and inositol 1,2,3,4,5,6-hexakisphosphate (IP 6 ) (12). Since the PH domain (or Btk homology domain) of Gap1 m is highly homologous to that of Btk (4, 13), Btk presumably binds these compounds. In this study, we show that Btk is an IP 4 -binding protein and that all of the XLA and Xid missense mutations in the PH domain result in dramatically reduced IP 4 binding activity. In addition, the constitutive activated form of Btk, which contains a point mutation (E41K) in the PH domain (14), binds IP 6 with higher affinity than normal Btk. On the basis of these findings, we discuss the role of IP 4 , IP 5 , and IP 6 binding to the PH domain of Btk in B cell development. 4 and inositol 1,4,5-trisphosphate (IP 3 ) were purchased from Boehringer Mannheim, and IP 5 and IP 6 were from Calbiochem. All other chemicals were commercial products of reagent grade. Solutions were prepared in deionized water. MATERIALS AND METHODS Chemicals-IPcDNA Cloning of Mouse Btk-cDNA encoding Btk (amino acids 1-659) from adult mouse spleen (BALB/c) was amplified by the reverse transcriptase polymerase chain reaction (PCR) (LA-PCR Kit; Takara Shuzo, Japan) for 40 cycles, each consisting of denaturation at 94°C for 1 min, annealing at 50°C for 2 min, and extension at 72°C for 3-4.5 min. The extension time was increased by 30 s every 10 cycles. The sense and antisense primer...

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Section: Discussionmentioning

confidence: 88%

Mutation of the Pleckstrin Homology Domain of Bruton's Tyrosine Kinase in Immunodeficiency Impaired Inositol 1,3,4,5-Tetrakisphosphate Binding Capacity

Fukuda

Kojima

Kabayama

et al. 1996

Journal of Biological Chemistry

204

177

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“…Moreover, importantly, the concentrations of exogenous GroPIns-4-P active on cAMP are in the low micromolar range (1-100 ,uM), which is also the range of the estimated concentration of GroPIns-4-P in Rastransformed thyroid cells (Iacovelli et al, 1993) and, most likely, of the levels of GroPIns-4-P formed intracellularly in response to EGF in fibroblasts (the latter are similar to those of Ins-1,4,5-P3, i.e., in the micromolar range; Irvine, 1989;Bunce et al, 1993;Mountford et al, 1994). Thus, collectively, the above findings argue rather compellingly that GroPIns-4-P formed by EGF can result in the inhibition of adenylyl cyclase.…”

Section: Discussionmentioning

confidence: 93%

Fast receptor-induced formation of glycerophosphoinositol-4-phosphate, a putative novel intracellular messenger in the Ras pathway.

Falasca

Carvelli

Iurisci

et al. 1997

MBoC

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Glycerophosphoinositols are phosphoinositide metabolites whose levels are constitutively elevated in Ras-transformed cells. Here, we show that one of these compounds, glycerophosphoinositol-4-phosphate (GroPlns-4-P) responds acutely to the stimulation of the epidermal growth factor receptor, with a fast, massive and transient increase. The mechanism leading to GroPIns-4-P formation involves the activation of phosphoinositide-3 kinase and the small GTP-binding protein Rac, since GroPIns-4-P was neither formed in cells expressing the dominant negative form of Rac nor in cells treated with the phosphoinositide-3 kinase inhibitor wortmannin. GroPIns-4-P has been previously shown to inhibit adenylyl cyclase. Accordingly, epidermal growth factor also decreased the basal, cholera toxin-stimulated, and forskolin-stimulated cyclic AMP levels with kinetics similar to those of GroPIns4-P formation, suggesting that GroPIns-4-P mediates this inhibitory effect. The hormone-induced formation of GroPIns-4-P was detected in several cell lines of various origin, suggesting that GroPIns4-P is a novel intracellular messenger of the Ras pathway, possibly able to convey information from tyrosine kinase receptors to the cyclic AMP cascade.

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“…The intracellular concentrations of GroPIns have also been confirmed by MS [12,13], showing that it varies across different cell types in the range of low-micromolar to almost millimolar levels (from 40 to 900 μM), and it can be modulated according to the state of cell stimulation, activation, differentiation and transformation [1,9,11,[14][15][16]. On the other hand, the intracellular levels of GroPIns4P and GroPIns(4,5)P 2 are at least 10-and 100-fold lower respectively than that of GroPIns, as can be extrapolated from HPLC analysis following cell extraction after equilibrium labelling with [ 3 H]myo-inositol (see [10] and references therein).…”

Section: Metabolism Of the Glycerophosphoinositolsmentioning

confidence: 87%

The glycerophosphoinositols and their cellular functions

Corda

Zizza

Varone

et al. 2012

Biochemical Society Transactions

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Interest in the glycerophosphoinositols has been increasing recently, on the basis of their biological activities. The cellular metabolism of these water-soluble bioactive phosphoinositide metabolites has been clarified, with the identification of the specific enzyme involved in their synthesis, PLA2IVα (phospholipase A2 IVα), and the definition of their phosphodiesterase-based catabolism, and thus inactivation. The functional roles and mechanisms of action of these compounds have been investigated in different cellular contexts. This has led to their definition in the control of various cell functions, such as cell proliferation in the thyroid and actin cytoskeleton organization in fibroblasts and lymphocytes. Roles for the glycerophosphoinositols in immune and inflammatory responses are also being defined. In addition to these physiological functions, the glycerophosphoinositols have potential anti-metastatic activities that should lead to their pharmacological exploitation.

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Intracellular concentrations of inositol, glycerophosphoinositol and inositol pentakisphosphate increase during haemopoietic cell differentiation

Cited by 35 publications

References 37 publications

Mutation of the Pleckstrin Homology Domain of Bruton's Tyrosine Kinase in Immunodeficiency Impaired Inositol 1,3,4,5-Tetrakisphosphate Binding Capacity

Mutation of the Pleckstrin Homology Domain of Bruton's Tyrosine Kinase in Immunodeficiency Impaired Inositol 1,3,4,5-Tetrakisphosphate Binding Capacity

Fast receptor-induced formation of glycerophosphoinositol-4-phosphate, a putative novel intracellular messenger in the Ras pathway.

The glycerophosphoinositols and their cellular functions

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