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The Journal of Neuroscience, December 3, 2003, 23(35):11224-11228

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Cellular/Molecular
Angiotensin II Blocks Nicotine-Mediated Neuroprotection against -Amyloid (1-42) via Activation of the Tyrosine Phosphatase SHP-1

Seán Shaw,¹ Merouane Bencherif,³ and Mario B. Marrero^1,2

¹Vascular Biology Center and ²Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, Georgia 30912, and ³Targacept Inc., Winston-Salem, North Carolina 27101-4165

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 -amyloid (1-42) [A (1-42)]. These results provided direct evidence for linkage between JAK2 and the 7 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 A (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 A (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 A (1-42) in PC12 cells are blocked by Ang II via AT₂ receptor-induced activation of SHP-1.

Key words: nicotine; neuroprotection; JAK2; phosphatydylinositol-3-kinase; SHP-1; PC12 cells; Alzheimer's disease; Ang II

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Received April 16, 2003; revised October 7, 2003; accepted October 10, 2003.

This article has been cited by other articles:

				M. C. Zatelli, D. Piccin, F. Tagliati, A. Bottoni, A. Luchin, and E. C. degli Uberti Src Homology-2-Containing Protein Tyrosine Phosphatase-1 Restrains Cell Proliferation in Human Medullary Thyroid Carcinoma Endocrinology, June 1, 2005; 146(6): 2692 - 2698. [Abstract] [Full Text] [PDF]

				R. K. Stumm, C. Zhou, S. Schulz, M. Endres, G. Kronenberg, J. P. Allen, G. Tulipano, and V. Hollt Somatostatin Receptor 2 Is Activated in Cortical Neurons and Contributes to Neurodegeneration after Focal Ischemia J. Neurosci., December 15, 2004; 24(50): 11404 - 11415. [Abstract] [Full Text] [PDF]

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