The phosphoinositide 3-kinase pathway

The Dictyostelium phosphoinositide 3-kinases have a domain organization similar to mammalian Class I phosphoinositide 3-kinases. They have an N-terminal domain that does not show much conservation, followed by a Ras-binding domain, a C2 domain, and a bipartite kinase domain. The involvement of phosphoinositide 3-kinases in polarized cellular responses suggested that their subcellular localization during chemotaxis might be important. Deletion analysis revealed that the N-terminal domain alone is required and sufficient for cAMP-induced 

For RaclB and its associated guanine nucleotide phosphataseactivating protein RacGapl, it has been shown that the activation state of Rac correlates with actin polymerization [34]. Either an increase or a reduction in the level of activated Rac is detrimental to chemotactic efficiency. The link to the cytoskeleton most likely involves p21-activated protein kinases and Wiskott-Aldrich syndrome protein family members that directly interact with activated racs. 

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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. 

Flsieh, A. C., R. Bo, J. Manola, F. Vazquez, O. Bare, A, Khvorova, S. Scaringe, and W. Sellers. 2004. A library of siRNA duplexes targeting the phosphoinositide 3-kinase pathway Determinants of gene silencing for use in cell-based screens. Nucleic Acids Res 32 893-901. 

Progress made in recent years has revealed the central role the phosphoinositide 3-kinase pathway plays in the establishment and the maintenance of cell polarity (Figure 7) [246]. The substrate for the Class I phosphoinositide 3-kinase [223] involved in chemotaxis is the membrane lipid phosphatidylinositol-(4, 5) bisphosphate, or PI(4,5)P2, which becomes phosphorylated at its 3 position to phosphatidylinositol-(3, 4, 5) trisphosphate, or PI(3, 4, 5)P3. A second 3-phosphoinositide, PI(3, 4)P2, can be formed by the dephosphorylation of PI(3, 4, 5)P3 at... 

Burke L et al (2005) Prognostic implications of molecular and immunohistochemical profiles of the Rb and p53 cell cycle regulatory pathways in primary non-small cell lung carcinoma. Clin Cancer Res 11 232-241 Cantley LC (2002) The phosphoinositide 3-kinase pathway. Science 296 1655-1657... 

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). 

Manning, B. D., and Cantley, L. C. (2003). United at last The tuberous sclerosis complex gene products connect the phosphoinositide 3-kinase/Akt pathway to mammalian target of rapamycin (mTOR) signaling. Biochem. Soc. Trans. 31, 573-578. 

Manning, B. D., Tee, A. R., Logsdon, M. N., Blenis, J., and Candey, L. C. (2002). Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. Mol. Cell 10, 151—162. 

Cantley, L.C., and Neel, B., 1999, New insights into tumor suppression PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/Akt pathway. Proc. Natl. Acad. Sci. 96 4240-4245. 

Wu, X., Senechal, K., Neshat, M.S., Whang, YE. and Sawyers, C.L. The PTEN/MMACl tumor suppressor phosphatase functions as a negative regulator of the phosphoinositide 3-kinase/Akt pathway (1998) Proc Natl Acad Sd U S A 95, 15587-91... 

The phosphoinositide-3 kinase (PI3-K)/Akt pathway is activated as a self-defense mechanism of RGCs against injuries inflicted by intravitreal injection of NMDA (Manabe and Lipton, 2003 Nakazawa et al., 2005), episcleral vein cauterization (Kanamori et al., 2004 Kim and Park, 2005), optic nerve clamping (Nakazawa et al., 2003), and translimbal photocoagulation (Levkovitch-Verbin et al., 2007). 

Shioi, T., Kang, P., Douglas, PS., Hampe, J., Yballe, C.M., Lawitts, J., Cantley, L.C., and Izumo, S. 2000. The conserved phosphoinositide 3-kinase pathway determines heart size in mice. Cell 19 2537-2548. 

Hou L, Klann E. 2004. Activation of the phosphoinositide 3-kinase-akt-mammalian target of rapamycin signaling pathway is required for metabotropic glutamate receptor-dependent long-term depression. J Neurosci 24 6352-6361. 

Control of dendritic arborization by the phosphoinositide-3 -kinase-akt-mammalian target of rapamycin pathway. J Neurosci 25 11300-11312. 

Sekulic, A., Hudson, C. C., Homme, J. L., Yin, P., Ottemess, D. M., Kamitz, L. M., andAbraham, R. T. (2000). A direct linkage between the phosphoinositide 3-kinase-AKT signaling pathway and the mammalian target of rapamycin in mitogen-stimulated and transformed cells. Cancer Res. 60, 3504-3513. 

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