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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

Department of Molecular and Cellular Biology (J.-M.L., M.M., K.T., H.T., J.I., L.-J.M., M.I., M.H.) Division of Medical Biochemistry and Cardiovascular Biology, Ehime University School of Medicine, Tohon, Ehime 791-0295, Japan; and Department of Cell Biology (C.N.), Institut Cochin, Institut National de la Santé et de la Recherche Médicale Unité 567-Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, 75014 Paris, France

Address all correspondence and requests for reprints to: Masatsugu Horiuchi, M.D., Ph.D., Department of Molecular and Cellular Biology, Division of Medical Biochemistry and Cardiovascular Biology, Ehime University School of Medicine, Shitsukawa, Tohon, Ehime 791-0295, Japan. E-mail: horiuchi{at}m.ehime-u.ac.jp.

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.

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