title: Angiotensin II-induced neural differentiation via angiotensin II type 2 (AT2) receptor-MMS2 cascade involving interaction between AT2 receptor-interacting protein and Src homology 2 domain-containing protein-tyrosine phosphatase 1.
abstract: Angiotensin II (Ang II) type 2 (AT2) receptors are abundantly expressed not only in the fetal brain where they probably contribute to brain development, but also in pathological conditions to protect the brain against stroke; however, the detailed mechanisms are unclear. Here, we demonstrated that AT2 receptor signaling induced neural differentiation via an increase in MMS2, one of the ubiquitin-conjugating enzyme variants. The AT2 receptor, MMS2, Src homology 2 domain-containing protein-tyrosine phosphatase 1 (SHP-1), and newly cloned AT2 receptor-interacting protein (ATIP) were highly expressed in fetal rat neurons and declined after birth. Ang II induced MMS2 expression in a dose-dependent manner, reaching a peak after 4 h of stimulation, and this effect was enhanced with AT1 receptor blocker, valsartan, but inhibited by AT2 receptor blocker PD123319. Moreover, we observed that an AT2 receptor agonist, CGP42112A, alone enhanced MMS2 expression. Neurons treated with small interfering RNA of MMS2 failed to exhibit neurite outgrowth and synapse formation. Moreover, the increase in AT2 receptor-induced MMS2 mRNA expression was enhanced by overexpression of ATIP but inhibited by small interfering RNA of SHP-1 and overexpression of catalytically dominant-negative SHP-1 or a tyrosine phosphatase inhibitor, sodium orthovanadate. After AT2 receptor stimulation, ATIP and SHP-1 were translocated into the nucleus after formation of their complex. Furthermore, increased MMS2 expression mediates the inhibitor of DNA binding 1 proteolysis and promotes DNA repair. These results provide a new insight into the contribution of AT2 receptor stimulation to neural differentiation via transactivation of MMS2 expression involving the association of ATIP and SHP-1.
authors.affiliation: Department of Molecular and Cellular Biology, Division of Medical Biochemistry and Cardiovascular Biology, Ehime University School of Medicine, Shitsukawa, Tohon, Ehime 791-0295, Japan.
authors.forename: Jian-Mei
authors.initials: JM
authors.lastname: Li
authors.forename: Masaki
authors.initials: M
authors.lastname: Mogi
authors.forename: Kana
authors.initials: K
authors.lastname: Tsukuda
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Tomochika
authors.forename: Jun
authors.initials: J
authors.lastname: Iwanami
authors.forename: Li-Juan
authors.initials: LJ
authors.lastname: Min
authors.forename: Clara
authors.initials: C
authors.lastname: Nahmias
authors.forename: Masaru
authors.initials: M
authors.lastname: Iwai
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Horiuchi
mesh_terms: D000804:Angiotensin II / Q000502:physiology*; D057912:Angiotensin II Type 2 Receptor Blockers; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000502:physiology; D002478:Cells, Cultured; D004260:DNA Repair; D007093:Imidazoles / Q000494:pharmacology; D051798:Inhibitor of Differentiation Protein 1 / Q000378:metabolism; D008025:Ligases / Q000378:metabolism*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D016501:Neurites / Q000502:physiology; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D054645:Protein Phosphatase 1; D021381:Protein Transport; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044139:Receptor, Angiotensin, Type 2 / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction; D013569:Synapses / Q000502:physiology; D013777:Tetrazoles / Q000494:pharmacology; D015533:Transcriptional Activation; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D000068756:Valsartan; D014638:Vanadates / Q000494:pharmacology
chemical_list: D057912:Angiotensin II Type 2 Receptor Blockers; D002352:Carrier Proteins; D007093:Imidazoles; D051798:Inhibitor of Differentiation Protein 1; C488664:Mtus1 protein, mouse; D009419:Nerve Tissue Proteins; D009842:Oligopeptides; D011725:Pyridines; D044139:Receptor, Angiotensin, Type 2; D013777:Tetrazoles; D025521:Tumor Suppressor Proteins; D000804:Angiotensin II; C060894:CGP 42112A; C073402:PD 123319; D014638:Vanadates; D000068756:Valsartan; D054645:Protein Phosphatase 1; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; C509250:Ptpn6 protein, rat; D008025:Ligases; C476410:Ube2v2 protein, rat; D014633:Valine