期刊
JOURNAL OF CELLULAR BIOCHEMISTRY
卷 103, 期 2, 页码 648-662出版社
WILEY
DOI: 10.1002/jcb.21439
关键词
G protein-coupled receptors; protein kinase C; phorbol esters
资金
- NIDDK NIH HHS [DK 55003, DK 56930, P30 DK041301, DK 41301] Funding Source: Medline
It is widely recognized that Hsp27 is a downstream substrate of the p38 MAP K cascade whereas the role of PKD family members in mediating receptor-stimulated Hsp27 Ser-82 phosphorylation has not been evaluated. Here, we show that neurotensin induced a rapid and striking increase in Hsp27 Ser-82 phosphorylation in PANC-1 cells, which was closely correlated with stimulation of activation loop phosphorylation of PKDs and p38 MAPK Thr180/Tyr182 phosphorylation. Treatment of PANC-1 cells with either the selective PKC inhibitor GF-I or the p38 MAPK inhibitor SB202190 partially reduced neurotensin-induced Hsp27 Ser-82 phosphorylation. However, treatment of the cells with a combination of GF-I and SB202190 virtually abolished neurotensin-induced Hsp27 Ser-82 phosphorylation. Overexpression of PKD in stably transfected PANC-1 cells increased the magnitude and prolonged the duration of Hsp27 Ser-82 phosphorylation in response to neurotensin. Either PKD or PKD2 gene silencing utilizing siRNAs targeting distinct PKD or PKD2 sequences reduced neurotensin-stimulated Hsp27 Ser-82 phosphorylation, but cotransfection of siRNAs targeting both, PKD and PKD2, markedly decreased neurotensin-induced Hsp27 Ser-82 phosphorylation. Knockdown of PKD and PKD2 abolished Hsp27 phosphorylation in cells treated with SB202190. Thus, neurotensin induces Hsp27 Ser-82 phosphorylation through p38 MAPK- and PKC/PKD-dependent pathways in PANC-1 cells. Our results demonstrate, for the first time, that neurotensin induces a striking increase in Hsp27 phosphorylation on Ser-82 in PANC-1 cells through convergent p38 MAPK, PKD, and PKD2 signaling.
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