ERK5 induces ankrd1 for catecholamine biosynthesis and homeostasis in adrenal medullary cells

Abstract

Extracellular signal-regulated kinases (ERKs) play important roles in proliferation, differentiation and gene expression. In our previous study, we demonstrated that both ERK5 and ERK1/2 were responsible for neurite outgrowth and tyrosine hydroxylase (TH) expression in rat pheochromocytoma cells (PC12) (J Biol Chem 284, 23,564-23,573, 2009). However, the functional differences between ERK5 and ERK1/2 signaling in neural differentiation remain unclear. In the present study, we show that ERK5, but not ERK1/2 regulates TH levels in rat sympathetic neurons. Furthermore, microarray analysis performed in PC12 cells using ERK5 and ERK1/2-specific inhibitors, identified ankyrin repeat domain 1 (ankrd1) as an ERK5-dependent and ERK1/2-independent gene. Here, we report a novel role of the ERK5/ankrd1 signaling in regulating TH levels and catecholamine biosynthesis. Ankrd1 mRNA was induced by nerve growth factor in time- and concentration-dependent manners. TH levels were reduced by ankrd1 knockdown with no changes in the mRNA levels, suggesting that ankrd1 was involved in stabilization of TH protein. Interestingly, ubiquitination of TH was enhanced and catecholamine biosynthesis was reduced by ankrd1 knockdown. Finally, we examined the relationship of ERK5 to TH levels in human adrenal pheochromocytomas. Whereas TH levels were correlated with ERK5 levels in normal adrenal medullas, ERK5 was down-regulated and TH was up-regulated in pheochromocytomas, indicating that TH levels are regulated by alternative mechanisms in tumors. Taken together, ERK5 signaling is required for catecholamine biosynthesis during neural differentiation, in part to induce ankrd1, and to maintain appropriate TH levels. This pathway is disrupted in pathological conditions.

Expression of Extracellular Signal-regulated Kinase 5 and Ankyrin Repeat Domain 1 in Composite Pheochromocytoma and Ganglioneuroblastoma Detected Incidentally in the Adult Adrenal Gland

“…However, ERK5- and ankrd1-positive tumor cells were scattered over both of the components in the composite tumor. These findings were consistent with our recent findings regarding human adrenal PC ( 38 ), suggesting that TH may be regulated not only by an ERK5/ankrd1 signaling cascade but also aberrantly by other unknown mechanisms.…”

“…The immunohistochemical staining methods ( 38 , 40 ) and fluorescence in-situ hybridization analyses used in the present report are described in detail in the supplementary file ( Supplementary file 2 ).…”

“…Very recently, we revealed for the first time that extracellular signal-regulated kinase 5 (ERK5) together with ankyrin repeat domain 1 (ankrd1) induced by ERK5 regulates tyrosine hydroxylase (TH) activity and catecholamine biosynthesis during neural differentiation, with ERK5 expression levels correlated with TH levels in the normal adrenal medulla ( 38 ). However, ERK5 was down-regulated, and the ERK5-mediated regulation of the cellular function was disrupted in human adrenal PC ( 38 ).…”

Midnolin is a novel regulator of parkin expression and is associated with Parkinson’s Disease

“…For examples, ERK5 was responsible for neurite outgrowth in PC12 cells and axon elongation in sympathetic neurons 6, 7 . In addition, the expression of tyrosine hydroxylase (TH) which is a rate-limiting enzyme for catecholamine biosynthesis was dramatically down-regulated by ERK5 knockdown in both cells, resulting in reduction in catecholamine biosynthesis.…”

Midnolin is a confirmed genetic risk factor for Parkinson’s disease

“…Previously, we have found that nerve growth factor (NGF) promotes neurite outgrowth and catecholamine biosynthesis in PC12 cells accompanied by activation of extracellular signal‐regulated kinases 1/2 and 5 . Furthermore, we revealed that MIDN is upregulated by NGF through these kinases, suggesting MIDN has essential roles in neuronal development.…”