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

Yutaro Obara, Ryusuke Nagasawa, Wataru Nemoto, Michael J. Pellegrino, Maho Takahashi, Beth A. Habecker, Philip J.S. Stork, Osamu Ichiyanagi, Hiromi Ito, Yoshihiko Tomita, Kuniaki Ishii, Norimichi Nakahata

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)177-189
Number of pages13
JournalCellular Signalling
Issue number3
StatePublished - Mar 1 2016


  • Ankyrin repeat domain 1 (ankrd1)
  • Extracellular-signal regulated kinase (ERK)
  • Nerve growth factor (NGF)
  • Pheochromocytoma
  • Sympathetic neurons
  • Tyrosine hydroxylase (TH)

ASJC Scopus subject areas

  • Cell Biology


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