ZPK inhibits PKA induced transcriptional activation by CREB and blocks retinoic acid induced neuronal differentiation

Abstract

Zipper Protein Kinase (ZPK) is a leucine zipper protein localized to the nucleus which exhibits serine-threonine kinase activity and is associated with the stress dependent signal transduction pathway. ZPK forms heterodimers with leucine zipper containing transcription factors such as the cyclic AMP responsive element binding protein (CREB) and Myc. Furthermore ZPK phosphorylates both Myc and CREB. Overexpression of ZPK in NTera-2 human teratocarcinoma cells results in inhibition of PKA induced transcriptional activation by CREB and prevents retinoic acid induced di erentiation of the cells to neurons. Our results suggest that ZPK sti¯es neural di erentiation of NT-2 cells partly due to its inhibitory e ect on CREB function.

Inhibition of membrane depolarisation-induced transcriptional activity of cyclic AMP response element binding protein (CREB) by the dual-leucine-zipper-bearing kinase in a pancreatic islet beta cell line

“…CREB activity induced by the adenylate cyclase activator forskolin was also reduced by cotransfection of the DLK expression vector (Fig. 3b), consistent with the previous study in NIH3T3 and NT2 teratocarcinoma cells [14]. However, in contrast to stimulation by membrane depolarisation (Fig.…”

“…In NIH3T3 and NTera-2 teratocarcinoma cell lines the overexpression of the human orthologue of DLK, ZPK, has been shown to inhibit CREB activity after stimulation by protein kinase A [14], which is confirmed by the present study in HIT beta cells. However, in contrast to stimulation by membrane depolarisation, protein kinase A-induced CREB activity was inhibited also by the kinase-dead mutant of DLK (present study), suggesting that the mechanism of inhibition by DLK may differ depending on the stimulus used.…”

“…However, in contrast to stimulation by membrane depolarisation, protein kinase A-induced CREB activity was inhibited also by the kinase-dead mutant of DLK (present study), suggesting that the mechanism of inhibition by DLK may differ depending on the stimulus used. ZPK is able to interact directly with CREB and to phosphorylate a CREB peptide that contains the CREB leucine zipper domain [14]. Although the functional consequences, if any, of these effects of DLK are unknown, they raise the possibility that protein kinase A might allow DLK-CREB interaction, which may interfere with CREB transactivation independently of the DLK kinase activity.…”

“…In the NIH3T3 and in a human teratocarcinoma cell line, protein kinase A-induced CREB activity was inhibited by the mitogen-activated protein kinase kinase kinase (MAPKKK) zipper protein kinase (ZPK), possibly by a direct interaction between CREB and ZPK [14]. However, the effect of ZPK on CREB activity in pancreatic islet beta cells was unknown.…”

Expression of cAMP response element-binding protein and sodium iodide symporter in benign non-functioning and malignant thyroid tumours

“…or not expressing CREB. Although we cannot establish at present whether reduced expression of CREB can play a role in the processes leading to neoplastic transformation or whether it is a consequence of it, it is worth mentioning that CREB transcriptional activity has been related to cell differentiation in different tissues, such as the brain and adipose tissue (25,26). Accordingly, a CREB gain-of-function mutant, which induced high levels of constitutive Ser 133 phosphorylation, was found to promote cell differentiation in vitro (27).…”