Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 279, Issue 16, Pages 16883-16893Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M313225200
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Funding
- NCI NIH HHS [P50 CA 90388] Funding Source: Medline
- NIDDK NIH HHS [DK55003, P30 DK 41301, DK56930] Funding Source: Medline
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Protein kinase D (PKD) potentiates cellular DNA synthesis in response to G protein-coupled receptor ( GPCR) agonists but the mechanism(s) involved has not been elucidated. Here, we examined whether PKD overexpression in Swiss 3T3 cells regulates the activation/inactivation kinetics of the extracellular-regulated protein kinase (ERK) in response to the mitogenic GPCR agonists bombesin and vasopressin. Addition of bombesin or vasopressin to Swiss 3T3 cells overexpressing PKD induced a striking increase in the duration of MEK/ ERK/RSK activation as compared with cultures of either control Swiss 3T3 cells or Swiss 3T3 cells expressing a kinase-inactive PKD mutant. In contrast, the duration of ERK activation in response to epidermal growth factor, which acts via protein kinase C/PKD-independent pathways, was not increased. Furthermore, bombesin or vasopressin promoted a striking increase in phosphorylation ( at Ser-374) and accumulation of c-Fos ( the c-fos proto-oncogene product) in Swiss 3T3 cells overexpressing wild-type ( but not kinase-inactive) PKD. Inhibition of the sustained phase of ERK/RSK activation abrogated the increase in c-Fos accumulation and DNA synthesis induced by bombesin or vasopressin in PKD-overexpressing cells. Our results demonstrate that PKD selectively potentiates mitogenesis induced by bombesin or vasopressin in Swiss 3T3 cells by increasing the duration of MEK/ ERK/RSK signaling.
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