Hematopoietic protein tyrosine phosphatase mediates beta2-adrenergic receptor-induced regulation of p38 mitogen-activated protein kinase in B lymphocytes.
Stimulation of the beta(2)-adrenergic receptor (beta(2)AR) 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 beta(2)AR stimulation mediates the increase in the level of p38 MAPK activation has remained unclear. Here we show that the beta(2)AR-induced increase in p38 MAPK activation occurred via a hematopoietic protein tyrosine phosphatase (HePTP)-mediated cross talk between PKA and p38 MAPK. beta(2)AR agonists, cAMP-elevating agents, and PKA inhibitors were used to show that beta(2)AR 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 beta-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, beta(2)AR 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.
McAlees
Jaclyn W
JW
Department of Molecular Virology, The Ohio State University, Columbus, Ohio 43210, USA.
Sanders
Virginia M
VM
D000818:Animals; D019390:Arrestins / Q000378:metabolism; D001402:B-Lymphocytes / Q000201:enzymology*; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D005260:Female; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000378:metabolism; D007073:Immunoglobulin E / Q000378:metabolism; D007074:Immunoglobulin G / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008954:Models, Biological; D010766:Phosphorylation; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000378:metabolism*; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
C000605258:Arrb2 protein, mouse; D019390:Arrestins; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D007074:Immunoglobulin G; D018343:Receptors, Adrenergic, beta-2; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D007073:Immunoglobulin E; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D054558:Protein Tyrosine Phosphatases, Non-Receptor; C502163:Ptpn7 protein, mouse; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D019205:GTP-Binding Protein alpha Subunits, Gs