Elevated expression of protein kinase C delta induces cell scattering upon serum deprivation.
Tumor metastasis might be evoked in response to microenvironmental stress, such as a shortage of oxygen. Although the cellular response to hypoxia has been well established, we know little about how tumors adapt themselves to deprivation of growth factor. Protein kinase Cdelta (PKCdelta), a stress-sensitive protein kinase, has been implicated in tumor progression. In this study, we demonstrate that elevated expression of PKCdelta in Madin-Darby canine kidney cells induces a scatter response upon serum starvation, a condition that mimics growth-factor deprivation. Serum starvation stimulates the catalytic activity and Y311 phosphorylation of PKCdelta through reactive oxygen species (ROS) and the Src family kinases. Mutation of PKCdelta at Y311 and Y322, both of which are phosphorylation sites for Src, impairs its activation and ability to promote cell scattering upon serum deprivation. Once activated by ROS, PKCdelta itself activates ROS production at least partially through NADPH oxidase. In addition, the c-Jun N-terminal kinase is identified as a crucial downstream mediator of ROS and PKCdelta for induction of cell scattering upon serum deprivation. We demonstrate that the C1B domain of PKCdelta is essential not only for its localization at the Golgi complex, but also for its activation and ability to induce cell scattering upon serum deprivation. Finally, depletion of PKCdelta in human bladder carcinoma T24 cells restores their cell-cell contacts, which thereby reverses a scattered growth pattern to an epithelial-like growth pattern. Collectively, our results suggest that elevated expression of PKCdelta might facilitate the scattering of cells in order to escape stress induced by growth-factor deprivation.
Chen
Chien-Lin
CL
Department of Life Science, National Chung Hsing University, Taichung, 40227, Taiwan.
Chan
Po-Chao
PC
Wang
Shang-Hwen
SH
Pan
Yi-Ru
YR
Chen
Hong-Chen
HC
D000818:Animals; D002450:Cell Communication / Q000502:physiology*; D002460:Cell Line; D016895:Culture Media, Serum-Free; D004285:Dogs; D006056:Golgi Apparatus / Q000201:enzymology; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000201:enzymology; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism; D010766:Phosphorylation; D051745:Protein Kinase C-delta / Q000096:biosynthesis / Q000172:deficiency / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000201:enzymology / Q000473:pathology; D019061:src-Family Kinases / Q000378:metabolism
D016895:Culture Media, Serum-Free; D017382:Reactive Oxygen Species; D019255:NADPH Oxidases; D019061:src-Family Kinases; D051745:Protein Kinase C-delta; D048670:MAP Kinase Kinase 4