Hematopoietic Protein Tyrosine Phosphatase Mediates β2-Adrenergic Receptor-Induced Regulation of p38 Mitogen-Activated Protein Kinase in B Lymphocytes
Hematopoietic Protein Tyrosine Phosphatase Mediates β2-Adrenergic Receptor-Induced Regulation of p38 Mitogen-Activated Protein Kinase in B Lymphocytes
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DOI：
10.1128/mcb.01466-08
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发表时间：
2009-02-01
影响因子：
5.3
通讯作者：
Sanders, Virginia M.
中科院分区：
文献类型：
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作者：
McAlees, Jaclyn W.;Sanders, Virginia M.
刺激CD40L/IL-4激活的B淋巴细胞上的β(2)肾上腺素能受体(β(2)AR)可增加蛋白激酶A(PKA)和p38丝裂原活化蛋白激酶(MAPK)依赖的免疫球蛋白E(IgE)水平。然而，β(2)AR刺激介导p38MAPK激活水平升高的机制尚不清楚。在这里，我们证明了β(2)AR诱导的p38MAPK激活的增加是通过造血蛋白酪氨酸磷酸酶(HePTP)介导的PKA和p38MAPK之间的相互作用。使用β(2)AR激动剂、cAMP提高剂和PKA抑制剂显示，β(2)AR刺激导致p38MAPK磷酸化水平依赖于PKA的增加。药理学药物和基因缺陷小鼠发现，p38MAPK的磷酸化受G刺激(Gs)/cAMP/PKA途径调节，而不受G抑制或β-arrestin-2途径的调节。免疫共沉淀和Western印迹分析表明，HePTP以PKA依赖的方式被磷酸化，这使HePTP失活，并允许增加的游离p38MAPK被CD40L激活的MAPK级联激活。HePTP短发夹状RNA证实了HePTP对B细胞p38MAPK磷酸化水平的调节作用。因此，B细胞上的β(2)AR刺激以Gs/cAMP/PKA依赖的方式磷酸化和失活HePTP，释放结合的p38MAPK，使其更有利于磷酸化和随后的IgE调节。
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.