Phosphatidylinositol 3, 4, 5 trisphosphate

The classical PTPs can be subdivided into receptorlike PTPs and nonreceptor, cytosolic PTPs. The second category of PTPs are broadly defined as dual specificity phosphatases (DSPs), which dephosphorylate pSer/ pThr as well as pTyr. MAP kinase phosphatases (MKPs) ( MAP kinase cascades) and PTEN are examples of DSP family members. Remarkably, PTEN also has lipid phosphatase activity that is specific for phosphatidylinositol-3,4,5-trisphosphate generated in response to the actions of PI3K. Finally, the class of low molecular mass (LM-) PTPs and that of CDC25 PTPs accomplish the cells repertoire of PTPs (Fig. 3). 

Arcaro, A., and Wymann, M. P. (1993). Wortmannin is a potent phosphatidylinositol 3-kinase inhibitor The role of phosphatidylinositol 3,4,5-trisphosphate in neutrophil responses. Biochem. J. 296, 297—301. 

More recently, the importance of a group of highly polar inositol lipids, present in neutrophils and many other cell types, has been recognised. Activation of neutrophils by fMet-Leu-Phe results in the transient accumulation of phosphatidylinositol 3-phosphate (Ptdlns 3-P), phosphatidylinositol 3,4-bisphosphate (Ptdlns 3,4-P2) and phosphatidylinositol 3,4,5-trisphosphate (Ptdlns 3,4,5-P3). Apparently, the enzyme phosphatidylinositol 3-hydroxy (3-OH) kinase plays a key role in the formation of these novel lipids. This enzyme can catalyse the formation of these lipids from phosphatidylinositol, phosphatidylinositol 4-phosphate (Ptdlns 4-P) and phosphatidylinositol 4,5 bisphosphate (Ptdlns 4,5-P2) in vitro (Fig. 6.10). Alternatively, it is possible that Ptdlns 3,4-P2 and Ptdlns 3-P are derived from the sequential dephosphorylation of Ptdlns 3,4,5-P3. 

Phosphatidylinositol bisphosphate is hydrolyzed to yield two intracellular messengers, diacylglycerol and inositol 1,4,5-trisphosphate. Phosphatidylinositol 3,4,5-trisphosphate is a nucleation point for supramolecular protein complexes involved in biological signaling. 

Nakanishi, H., K.A. Brewer, and J.H. Exton. 1993. Activation of the zeta isozyme of protein kinase C by phosphatidylinositol 3,4,5-trisphosphate. J. Biol. Chem. 268 13-16. 

Maehama, T., and Dixon, J.E. (1998). The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem 273, 13375-13378. 

Fig. 1. Schematic representations of D-phosphatidylinositol 3-phosphate [PtdIns(3)P], D-phosphatidylinositol 3,4-bisphosphate [PtdIns(3,4)P2] and D-phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P3].

Pesesse, X., Moreau, C., Drayer, A.L., Woscholski, R, Parker, P., and Emeux, C. 1998, The SH2 domain containing inositol 5-phosphatase SHIP2 displays phosphatidylinositol 3,4,5 trisphosphate and inositol 1,3,4,5 tetrakisphosphate 5-phosphatase activity. FEES Lett. 

Freeburn, R.W., Wright, K.L., Burgess, S.J., Astoul, E., Cantrell, D.A., and Ward, S.G., 2002, Evidence that SHIP-1 contributes to phosphatidylinositol 3,4,5-trisphosphate metabolism inT lymphocytes and can regulate novel phosphoinositide 3-kinase effectors. J. Immunol. 169 5441-5450. 

Bodin S, Giuriato S, Ragab J, Humbel BM, Viala C, Vieu C, Chap H, Payrastre B. Production of phosphatidylinositol 3,4,5-trisphosphate and phosphatidic acid in platelet rafts evidence for a critical role of cholesterol-enriched domains in human platelet activation. Biochemistry 2001 40 15290-15299. 

PKC is rapidly activated by a a transient rise in DAG levels resulting from PLC stimulation. Phospholipase D (PLD) causes phosphatidylcholine hydrolysis, which results in an increase in DAG and PKC activity. Phosphatidylinositol 3,4,5-trisphosphate (PIP3), an other lipid metabolite, can activate PKC. 

Proteins and ligands interacting with the domains are shown above. PIP3 phosphatidylinositol (3,4,5) trisphosphate. 

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