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首页> 外文期刊>Molecular and Cellular Biology >Hematopoietic Protein Tyrosine Phosphatase Mediates β2-Adrenergic Receptor-Induced Regulation of p38 Mitogen-Activated Protein Kinase in B Lymphocytes
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Hematopoietic Protein Tyrosine Phosphatase Mediates β2-Adrenergic Receptor-Induced Regulation of p38 Mitogen-Activated Protein Kinase in B Lymphocytes

机译：造血蛋白酪氨酸磷酸酶介导β2-肾上腺素能受体诱导的B淋巴细胞中p38丝裂原活化蛋白激酶的调控。

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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.
机译：在CD40L /白介素4激活的B淋巴细胞上刺激β 2 -肾上腺素受体（β 2 AR）会增加蛋白质中免疫球蛋白E（IgE）的水平激酶A（PKA）和p38丝裂原活化蛋白激酶（MAPK）依赖的方式。然而，β 2 AR刺激介导p38 MAPK激活水平增加的机制仍不清楚。在这里，我们显示β 2 AR诱导的p38 MAPK活化是通过造血蛋白酪氨酸磷酸酶（HePTP）介导的PKA与p38 MAPK之间的串扰发生的。 β 2 AR激动剂，cAMP升高剂和PKA抑制剂被用于显示β 2 AR刺激导致p38 MAPK磷酸化的PKA依赖性增加。药理作用剂和基因缺陷小鼠显示，p38 MAPK磷酸化受G刺激（Gs）/ cAMP / PKA途径调节，与G抑制或β-arrestin-2途径无关。免疫共沉淀和蛋白质印迹分析表明，HePTP以PKA依赖性方式被磷酸化，从而使HePTP失活，并使增加的游离p38 MAPK被CD40L激活的MAPK级联磷酸化。 HePTP短发夹RNA证实HePTP在调节B细胞中p38 MAPK磷酸化水平中发挥了作用。因此，B细胞上的β 2 AR刺激以Gs / cAMP / PKA依赖性方式磷酸化HePTP并使之失活，从而释放结合的p38 MAPK，从而为磷酸化和随后的IgE调控提供了更多的机会。

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