3-phosphoinositide-dependent protein kinase-1 regulates proliferation and survival of cancer cells with an activated mitogen-activated protein kinase pathway.
Engagement of cell surface receptor tyrosine kinases by insulin and growth factors activates phosphatidylinositol 3-kinase (PI3K) and generates the second messenger, phosphatidylinositol 3,4,5-trisphosphate. This second messenger leads to the recruitment of 3-phosphoinositide-dependent protein kinase-1 (PDK1) to the proximal side of the plasma membrane, which results in the activation of AKT kinase. In addition, PDK1 can phosphorylate numerous other kinases, including p90RSK, a kinase downstream of mitogen-activated protein kinase (MAPK) that is important for cell proliferation and survival. Previous studies have shown that the loss of PDK1 sensitizes tumor cells to chemotherapeutic agents and radiation but have not focused on delineating the contribution of PDK1 to pathway-specific mutations associated with various cancers other than the PI3K/AKT pathway. In this study, we show that the reduction of PDK1 by RNAi in melanoma and colon cancer cell lines activated in the MAPK pathway results in significant cell growth inhibition and apoptosis. Furthermore, PDK1 reduction in tumor cells resulted in impaired PAK kinase signaling, altered actin polymerization, and reduced cell migration. These studies show that PDK1 plays a pivotal role in MAPK and PI3K signaling in tumor cells.
Lu
Zhuomei
Z
Schering-Plough Research Institute, Kenilworth, NJ 07033, USA.
Cox-Hipkin
Mary Ann
MA
Windsor
William T
WT
Boyapati
Anita
A
D064413:3-Phosphoinositide-Dependent Protein Kinases; D017209:Apoptosis / Q000235:genetics; D002277:Carcinoma / Q000201:enzymology / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D003110:Colonic Neoplasms / Q000201:enzymology / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D004789:Enzyme Activation / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics; D008545:Melanoma / Q000201:enzymology / Q000235:genetics; D009369:Neoplasms / Q000201:enzymology* / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference / Q000502:physiology
D064413:3-Phosphoinositide-Dependent Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D018129:Phosphatidylinositol Phosphates; D017346:Protein Serine-Threonine Kinases; C060974:phosphatidylinositol 3,4,5-triphosphate; C578562:PDPK1 protein, human