Functional links between diacylglycerol and phosphatidylinositol signaling systems in human leukocyte-derived cell lines.
In leukocytes, diacylglycerol (DAG) regulates the small GTPase Ras through the agency of Ras guanyl releasing proteins (RasGRPs). Ras is thought to regulate phosphatidylinositol 3-kinase (PI3K). Therefore, DAG signaling is hypothesized to impact PI3K activity. The DAG analogue "pico" was used to activate RasGRPs in leukocyte-derived cell lines. PI3K signaling was monitored using antibodies that recognize the activated form of the PI3K-regulated protein kinase Akt. Diverse responses were documented. Some cell lines exhibit a DAG analogue-stimulated increase in phospho-Akt but this response proceeded even when Ras activation was blocked. In some Epstein-Barr virus-associated malignant cell lines and transformed B cells, high basal phospho-Akt was decreased by DAG analogue treatment. The pan-PKC inhibitor Bisindolymaleimide I blocked this effect. Basal phospho-Akt was also decreased by treatment with Go6976, an inhibitor of conventional protein kinase C and protein kinase D. While the proposed RasGRP-Ras-PI3K-Akt signaling axis may operate in some situations, our results indicate that alternative links between DAG targets such as protein kinases and the PI3K signaling system are more prominent.
Poon
Ho Y
HY
Department of Biochemistry, University of Alberta, Edmonton Alberta, Canada T6G 2H7.
Stone
James C
JC
D002460:Cell Line; D045744:Cell Line, Tumor; D004075:Diglycerides / Q000378:metabolism*; D006801:Humans; D007962:Leukocytes / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010716:Phosphatidylinositols / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D018631:ras Proteins / Q000378:metabolism
D004075:Diglycerides; D010716:Phosphatidylinositols; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D018631:ras Proteins