Growth factors, phosphatidylinositol

Zhong, H., Chiles, K., Feldser, D., Laughner, E., Hanrahan, C., Georgescu, M. M., Simons, J. W., and Semenza, G. L. (2000). Modulation of hypoxia-inducible factor 1-alpha expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/ FRAP pathway in human prostate cancer cells Implications for tumor angiogenesis and therapeutics. Cancer Res. 60, 1541-1545. 

Family of enzymes phosphorylating phosphatidylinositol (Ptdlns), PtdIns(4)phosphate, and PtdIns(4,5)phosphate in the 3-position. The Ptdlns(3 phospholipids are second messengers in processes like cell growth, cytoskeletal rearrangement, and vesicular transport. PI 3-kinases are heterodimers composed of a catalytic and a regulatory subunit. The enzymes are activated by insulin, many growth factors, and by a variety of cytokines. Their activity can be inhibited by wortmannin and LY294002. 

Bagli E, Stefaniotou M, Morbidelli L, Ziche M, Psillas K, Murphy C and Fotsis T. 2004. Luteolin inhibits vascular endothelial growth factor-induced angiogenesis inhibition of endothelial cell survival and proliferation by targeting phosphatidylinositol 3 -kinase activity. Cancer Res 64(21) 7936-7946. 

Gerber HP, McMurtrey A, Kowalski J, et al. Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3-kinase/Akt signal transduction pathway requirement for Flk-l/KDR activation. J Biol Chem 1998 273(46) 30,336-30,343. 

Soltoff SP, Carraway KL, 3rd, Prigent SA et al. ErbB3 is involved in activation of phosphatidylinositol 3-kinase by epidermal growth factor. Mo/ Cell Biol 1994 14 3550-3558. 

Hu P, Margolis B, Skolnik EY et al. Interaction of phosphatidylinositol 3-kinase-associated p85 with epidermal growth factor and platelet-derived growth factor receptors. Mo/ Cell Biol 1992 12 981-990. Li N, Batzer A, Daly R et al. Guanine-nucleotide-releasing factor hSosl binds to Grb2 and links receptor tyrosine kinases to Ras signalling. Nature 1993 363 85-88. 

Fig. 3. A simplified illustration of BCR-ABL and SRC family kinase involvement in oncogenic signaling pathways. The inhibitory effect is indicated by the upside-down T s. ABL = Abelson tyrosine kinase BCR = breakpoint cluster region FAK = focal adhesion kinase Grb-2 = growth factor receptor-bound protein 2 HcK = hematopoietic cell kinase JNK = Jun amino-terminal kinase P = phosphate group PI3 K = phosphatidylinositol-3-kinase SFK = SRC family kinases StatS = signal transducer and activator of transcription 5. (Reprinted with permission from Ref (123)). 

Chakravorty, A. Joslyn, M.L Davis, J.S. Characterization of insulin and insulin-like growth factor-I actions in the bovine luteal cell Regulation of receptor tyrosine kinase activity, phosphatidylinositol 3-kinase, and deoxyribonucleic acid synthesis. Endocrinology, 133, 1331-1340 (1993)... 

Fujioka, T. Ui, M. Involvement of insulin receptor substrates in epidermal growth factor induced activation of phosphatidylinositol 3-kinase in rat hepatocyte primary culture. Eur. J. Biochem., 268, 25-34 (2001)... 

Yu, Y Sato, J.D. MAP kinases, phosphatidylinositol 3-kinase, and p70 S6 kinase mediate the mitogenic response of human endothelial cells to vascular endothelial growth factor. J. Cell. Physiol., 178, 235-246 (1999)... 

Phospholipase C, which initiates the release of phosphatidylinositol derivatives, also requires Ca2+ for activity. It is difficult to determine whether release of Ca2+ is a primary or secondary response. There are three isoenzyme types of phospholipase C-(3, y, and 8- and several sub forms of each with a variety of regulatory mechanisms.298 3"" For example, the y isoenzymes are activated by binding to the tyrosine kinase domain of receptors such as that for epidermal growth factor (see Fig. 11-13). In contrast, the (3 forms are often activated by inhibitory G proteins and also by G, which is specific for inositol phosphate release. 

Apart from PKA, some other protein-kinases were found to be controlled by forskolin, such as cytosolic sphingosine kinase in rat periosteal cells [186] and protein kinase B (PKB) [187]. The latter was found to be stimulated by the activation of PKA through a PI3 (phosphatidylinositol 3)-kinase-independent pathway. Furthermore, a distinct activation mechanism was suspected, other than that normally observed by growth factors such as insulin, since substitution of the serine at the S473 position of PKB with alanine could not prevent activation by forskolin. The JAK family of protein kinases in T lymphocytes can also be regulated by forskolin through the activation of PKA [188]. Thus it seems obvious that many other enzymes could be susceptible to control by forskolin. 

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