Signaling pathways phosphatidylinositol-3-kinases

K18. Koh, J. S., Lieberthal, W., Heydrick, S., and Levine, J. S., Lysophosphatidic acidis a major serum noncytokine survival factor for murine macrophages which acts via the phosphatidylinositol 3-kinase signaling pathway. J. Clin. Invest. 15,716—727 (1998). 

M.A. Webster, J.N. Hutchinson, M.J. Rauh, S.K. Muthuswamy, M. Anton, C.G. Tortorice, R.D. Cardiff, F.L. Graham, J.A. Hassell and W.J. Muller, Requirement for both She and phosphatidylinositol 3 kinase signaling pathways in polyomavirus middle T-mediated mammary tumorigenesis. Mol Cell Biol, 18 (1998) 2344-2359. 

After activation of the TCR, there is induction of Src family tyrosine kinase (p56lek), which phosphorylates phospholipase Oyl. This is followed by the hydrolysis of phosphatidylinositol 4,5-bisphosphate, resulting in the production of diacyl-glycerol (DAG) and inositol trisphosphate (IP3). Protein kinase C is activated by DAG, which phosphorylates Ras. Ras is a GTPase and its phosphorylation induces Raf and initiation of MAP kinase signaling pathway. IP3 is involved in calcium-dependent activation of IL-2 gene expression via nuclear factor of activated T cells (NFAT). 

Munnik, T., Irvine, R.F. and Musgrave, A., 1994, Rapid turnover of phosphatidylinositol 3-phosphate in the green alga Chlamydomonas eugametos signs of a phosphatidylinositide 3-kinase signaling pathway in lower plants Biochem. J. 298 269-273. 

Hawes BE, LUTTRELL LM, van BBESEN T, LEFKOWITZ RJ. Phosphatidylinositol 3-kinase is an early intennediate in (he GPy-mediated mitogen-activated protein kinase signalling pathway. JBiol Chem 271 12133-12136,1996. 

Ptasznik, A., Prossnitz, E.R., Yoshikawa, D., Smreka, A., Traynor-Kaplan, A.E. and Rokoch, G.M. (1996). A tyrosine kinase signaling pathway accounts for the majority of phosphatidylinositol 3,4,5-trisphosphate formation in chemoattractant-stimulated human neutrophils./. Biol. Chem. 271, 25204-25207. 

Logan SK, Falaska M, Hu P, Schlessinger J. Phosphatidylinositol 3-kinase mediates epidermal growth factor-induced activation of the c-Jun N-terminal kinase signaling pathway. Mol Cell Biol 1997 17 5784-5790. 

Number of papers to date have shown that the CXCR4 receptors expressed in both neuronal and glial cells are functional and coupled to multiple intracellular pathways (Lazarini et al. 2003). The CXCR4 through pertussis toxin (PTX)- sensitive G proteins is coupled to at least two distinct signaling pathways (1) the first pathway, involving the activation of phosphatidylinositol- 3 (PI-3) kinase and extracellular signal... 

Recent studies in a model of ischemic stroke suggest that the acute neuro-protective effect of melatonin involves activation of the phosphatidylinositol-3-kinase/Akt pathway, whereas ERK-1/2 and c-Jun N-terminal kinase-1/2, in addition to Akt signaling, appear to be involved in its long-term effects (Kilic et al. 2005). These results indicate that melatonin can interact with multiple cellular pathways to produce its diverse physiological effects. Moreover, MTi and MT2 receptors can interact with divergent signaling pathways, as shown by their ability to... 

FIGURE 14-6 Main signaling pathways for histamine receptors. Histamine can couple to a variety of G-protein-linked signal transduction pathways via its four different receptors. The Hj receptor activates the phosphatidylinositol turnover via Gq/11 proteins. The other receptors either positively (H2 receptor) or negatively (H3 and H4 receptor) regulate adenylyl cyclase activity via Gs and GUo protein activation respectively. Several additional signaling pathways have been described, which are not shown. Abbreviations PfP2, phosphatidylinositol 4,5-bisphosphate PIC, phospholipase C AC, adenylyl cyclase ATP, adenosine triphosphate cAMP, cyclic AMP PKC, protein kinase C PICA, protein kinase A. 

Carson, J.P., KuUk, G., Weber, M.J. 1999, Antiapoptotic signaling in LNCaP prostate cancer cells a survival signaling pathway independent of phosphatidylinositol 3 -kinase and Akt/protein kinase B. Cancer Res Apr 59 1449-1453... 

The Ras to Raf to Erk signaling pathway depicted in fignre 24.1 is important but it is not the most important signaling pathway associated with development of human tumors, particularly those tumors that are most frequently fatal to cancer patients. That honor goes to the phosphatidylinositol-3-kinase, P13K, signaling pathway. This pathway is complex and 1 shall not describe it. 

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)). 

Phosphorylated IRS-1 activates a second signaling pathway by interacting with an 85-kDa SH2-containing protein that is a subunit of phophatidylinositol 3-kinase.384 386 This activates the 110-kDa catalytic subunit of the 3-kinase, which catalyzes formation of phosphatidylinositol 3-phosphate as well as Ptdlns (3,4)P2 and Ptdlns (3,4,5)P3.387/387a These compounds, which remain within membranes, activate other branches of the signaling cascade, some of which may converge with those of the MAP kinase cascade. However, there appears to be specific activation of a ribosomal Ser/Thr kinase that, among other activities, phosphorylates ribosomal protein S6, a component of the small ribosomal subunit.388 It also phosphorylates some isoforms of protein kinase C and other enzymes. Ptdlns 3-kinase may also activate 6-phosphofructo-2-kinase (Fig. 11-2, step ti).384/388... 

The Ca2+-phosphoinositide signaling pathway. Key proteins include hormone receptors (R), a G protein (G), a phosphoinositide-specific phospholipase C (PLC), protein kinase C substrates of the kinase (S), calmodulin (CaM), and calmodulin-binding enzymes (E), including kinases, phosphodiesterases, etc. (PIP2, phosphatidylinositol-4,5-bisphosphate DAG, diacylglycerol. Asterisk denotes activated state. Open arrows denote regulatory effects.)... 

Fig. 15.1. Signal pathways activated or inhibited by BCR-ABL oncoprotein. The figure shows some of all the downstream signalling pathways of BCR-ABL note, more molecules which interact with BCR-ABL have been reported. GRB2, growth factor receptor-bound protein 2 PI3K, phosphatidylinositol 3-kinase ICSBP, interferon consensus sequence binding protein.

Recendy, the phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway has been implicated in hypersensitivity induced by SNL (Xu et al., 2007). We investigated the possible involvement of this pathway in the antinociceptive effects of... 

---