Angiotensin II-Induced Neural Differentiation via Angiotensin II Type 2 (AT₂) Receptor-MMS2 Cascade Involving Interaction between AT₂Receptor-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.

Direct Stimulation of Angiotensin II Type 2 Receptor Enhances Spatial Memory

“…In this study, we observed that direct stimulation of the AT 2 receptor enhanced neurite elongation in hippocampal neurons. Moreover, AT 2 receptor stimulation directly enhances synaptic plasticity as reported previously (Li et al, 2005(Li et al, , 2007Reinecke et al, 2003). Therefore, the increase in f-EPSP observed in the hippocampus of mice treated with C21 could be caused by neurite elongation, synaptic augmentation, and increased electrotonic coupling.…”

Angiotensin-II-induced apoptosis requires regulation of nucleolin and Bcl-xL by SHP-2 in primary lung endothelial cells

“…The contradictory effect of Ang II on cellular proliferation versus apoptosis has been hypothesized to be determined by cell-typespecific expression of the receptors as well as differences in downstream signaling. The activation of SHP-1 and SHP-2 protein phosphatases is considered one of the most crucial downstream effects of Ang II, and is believed to mediate negative crosstalk between AT2 with AT1 and possibly with other growth-factor receptors (Alvarez et al, 2008;Bedecs et al, 1997;Cui et al, 2001;Li et al, 2007;Marrero et al, 1998;Matsubara et al, 2001;Wu et al, 2004). In some cells, it has been demonstrated that Ang-II treatment activates opposing signals through simultaneous AT1 and AT2 activation.…”

The renin-angiotensin system meets the hallmarks of cancer

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