Angiotensin II blocks nicotine-mediated neuroprotection against beta-amyloid (1-42) via activation of the tyrosine phosphatase SHP-1.
We showed recently that nicotine activates the growth-promoting enzyme Janus kinase 2 (JAK2) in PC12 cells and that preincubation of these cells with the JAK2-specific inhibitor AG-490 blocked the nicotine-induced neuroprotection against beta-amyloid (1-42) [Abeta (1-42)]. These results provided direct evidence for linkage between JAK2 and the alpha7 nicotinic acetylcholine receptor-induced neuroprotection in PC12 cells. We also showed that preincubation with angiotensin II (Ang II), functioning via the angiotensin II type 2 (AT2) receptor, blocked both the nicotine-induced activation of JAK2 and its neuroprotection against Abeta (1-42). Recently growth-inhibitory effects of the AT2 receptor have been reported to be mediated by the activation of protein tyrosine phosphatases (PTPases) and that AT2 receptor stimulation is associated with a rapid activation of the PTPase SHP-1 (the cytoplasmic tyrosine phosphatase that contains Src homology 2 domains), a negative regulator of JAK2 signaling. Therefore, the potential biological significance of AT2 receptor-induced effects on both the nicotine-induced activation of JAK2 and its neuroprotection against Abeta (1-42) led us to investigate whether SHP-1 activation could be involved in this process. We found that Ang II induced the activation of SHP-1 and that an antisense against SHP-1 not only augmented the nicotine-induced tyrosine phosphorylation of JAK2 but also blocked the Ang II neutralization of the nicotine-induced neuroprotection. These results demonstrate that nicotine-induced tyrosine phosphorylation of JAK2 and neuroprotection against Abeta (1-42) in PC12 cells are blocked by Ang II via AT2 receptor-induced activation of SHP-1.
Shaw
Seán
S
Vascular Biology Center, Medical College of Georgia, Augusta, Georgia 30912, USA.
Bencherif
Merouane
M
Marrero
Mario B
MB
D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis; D004336:Drug Antagonism; D004789:Enzyme Activation / Q000187:drug effects; D047908:Intracellular Signaling Peptides and Proteins; D053614:Janus Kinase 2; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009538:Nicotine / Q000494:pharmacology*; D016716:PC12 Cells; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D010673:Pheochromocytoma / Q000188:drug therapy / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D051381:Rats; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism
D016229:Amyloid beta-Peptides; D047908:Intracellular Signaling Peptides and Proteins; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D044139:Receptor, Angiotensin, Type 2; C075222:amyloid beta-protein (1-42); D000804:Angiotensin II; D009538:Nicotine; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; C507927:Jak2 protein, rat; D053614:Janus Kinase 2; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C509250:Ptpn6 protein, rat