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Molecular and Cellular Biology, February 2009, p. 675-686, Vol. 29, No. 3
0270-7306/09/$08.00+0     doi:10.1128/MCB.01466-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Hematopoietic Protein Tyrosine Phosphatase Mediates β2-Adrenergic Receptor-Induced Regulation of p38 Mitogen-Activated Protein Kinase in B Lymphocytes{triangledown}

Jaclyn W. McAlees1,2 and Virginia M. Sanders2*

Integrated Biomedical Science Graduate Program,1 Department of Molecular Virology, Immunology, and Medical Genetics, the Ohio State University, 333 West 10th Avenue, Columbus, Ohio 432102

Received 18 September 2008/ Accepted 19 November 2008

Stimulation of the β2-adrenergic receptor (β2AR) on a CD40L/interleukin-4-activated B lymphocyte increases the level of immunoglobulin E (IgE) in a protein kinase A (PKA)- and p38 mitogen-activated protein kinase (MAPK)-dependent manner. However, the mechanism by which β2AR stimulation mediates the increase in the level of p38 MAPK activation has remained unclear. Here we show that the β2AR-induced increase in p38 MAPK activation occurred via a hematopoietic protein tyrosine phosphatase (HePTP)-mediated cross talk between PKA and p38 MAPK. β2AR agonists, cAMP-elevating agents, and PKA inhibitors were used to show that β2AR stimulation resulted in a PKA-dependent increase in p38 MAPK phosphorylation. Pharmacological agents and gene-deficient mice revealed that p38 MAPK phosphorylation was regulated by the G-stimulatory (Gs)/cAMP/PKA pathway independently of the G-inhibitory or β-arrestin-2 pathways. Coimmunoprecipitation and Western blot analysis showed that HePTP was phosphorylated in a PKA-dependent manner, which inactivated HePTP and allowed for increased free p38 MAPK to be phosphorylated by the MAPK cascade that was activated by CD40L. HePTP short hairpin RNA confirmed that HePTP played a role in regulating the level of p38 MAPK phosphorylation in a B cell. Thus, β2AR stimulation on a B cell phosphorylates and inactivates HePTP in a Gs/cAMP/PKA-dependent manner to release bound p38 MAPK, making more available for phosphorylation and subsequent IgE regulation.

* Corresponding author. Mailing address: The Ohio State University, Department of Molecular Virology, Immunology, and Medical Genetics, 1190 Graves Hall, 333 West 10th Avenue, Columbus, OH 43210. Phone: (614) 292-4986. Fax: (614) 292-6805. E-mail: virginia.sanders{at}osumc.edu

{triangledown} Published ahead of print on 1 December 2008.

Molecular and Cellular Biology, February 2009, p. 675-686, Vol. 29, No. 3
0270-7306/09/$08.00+0     doi:10.1128/MCB.01466-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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