title: 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.
authors.affiliation: Department of Cellular Signaling, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba 6-3, Aramaki, Aoba-ku, Sendai 980-8578, Japan; Department of Pharmacology, Yamagata University School of Medicine, Iida-Nishi 2-2-2, Yamagata 990-9585, Japan. Electronic address: obaray@med.id.yamagata-u.ac.jp.
authors.forename: Yutaro
authors.initials: Y
authors.lastname: Obara
authors.affiliation: Department of Cellular Signaling, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba 6-3, Aramaki, Aoba-ku, Sendai 980-8578, Japan.
authors.forename: Ryusuke
authors.initials: R
authors.lastname: Nagasawa
authors.affiliation: Department of Cellular Signaling, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba 6-3, Aramaki, Aoba-ku, Sendai 980-8578, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Nemoto
authors.affiliation: Department of Physiology and Pharmacology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239-3098, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Pellegrino
authors.affiliation: The Vollum Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239-3098, USA.
authors.forename: Maho
authors.initials: M
authors.lastname: Takahashi
authors.affiliation: Department of Physiology and Pharmacology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239-3098, USA.
authors.forename: Beth A
authors.initials: BA
authors.lastname: Habecker
authors.affiliation: The Vollum Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239-3098, USA.
authors.forename: Philip J S
authors.initials: PJS
authors.lastname: Stork
authors.affiliation: Department of Urology, Yamagata University School of Medicine, Iida-Nishi 2-2-2, Yamagata 990-9585, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Ichiyanagi
authors.affiliation: Department of Urology, Yamagata University School of Medicine, Iida-Nishi 2-2-2, Yamagata 990-9585, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Ito
authors.affiliation: Department of Urology, Yamagata University School of Medicine, Iida-Nishi 2-2-2, Yamagata 990-9585, Japan.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Tomita
authors.affiliation: Department of Pharmacology, Yamagata University School of Medicine, Iida-Nishi 2-2-2, Yamagata 990-9585, Japan.
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Ishii
authors.affiliation: Department of Cellular Signaling, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba 6-3, Aramaki, Aoba-ku, Sendai 980-8578, Japan.
authors.forename: Norimichi
authors.initials: N
authors.lastname: Nakahata
mesh_terms: D000293:Adolescent; D000310:Adrenal Gland Neoplasms / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002395:Catecholamines / Q000032:analysis / Q000096:biosynthesis*; D002851:Chromatography, High Pressure Liquid; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D006801:Humans; D008297:Male; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048054:Mitogen-Activated Protein Kinase 7 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009124:Muscle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020932:Nerve Growth Factor / Q000494:pharmacology; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016716:PC12 Cells; D010673:Pheochromocytoma / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D053719:Tandem Mass Spectrometry; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C491303:Ankrd1 protein, rat; D002395:Catecholamines; D009124:Muscle Proteins; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D020932:Nerve Growth Factor; D014446:Tyrosine 3-Monooxygenase; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048054:Mitogen-Activated Protein Kinase 7
keywords: Ankyrin repeat domain 1 (ankrd1); Extracellular-signal regulated kinase (ERK); Nerve growth factor (NGF); Pheochromocytoma; Sympathetic neurons; Tyrosine hydroxylase (TH)