Activation of nuclear factor κB by somatostatin type 2 receptor in pancreatic acinar AR42J cells involves Gα14 and multiple signaling components -: A mechanism requiring protein kinase C, calmodulin-dependent kinase II, ERK, AND c-Src
Activation of nuclear factor κB by somatostatin type 2 receptor in pancreatic acinar AR42J cells involves Gα14 and multiple signaling components -: A mechanism requiring protein kinase C, calmodulin-dependent kinase II, ERK, AND c-Src
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DOI：
10.1074/jbc.m504264200
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发表时间：
2005-10-14
影响因子：
4.8
通讯作者：
Wong, YH
中科院分区：
文献类型：
--
作者：
Liu, AMF;Wong, YH
靶向生长抑素2型受体（SSTR 2）的药物已经用于胰腺炎症和癌症，可能通过调节转录因子核因子κ B（NF κ B）。在这里，我们证明了在肿瘤胰腺腺泡AR 42 J细胞中，SSTR 2的激活导致通过百日咳毒素不敏感的G蛋白以时间和剂量依赖性方式刺激抑制剂κ B激酶（IKK）/ NF κ B信号级联。G（q/11）和G（12/13）蛋白在转染的人胚肾293细胞中不能通过SSTR 2激活IKK/NF κ B，而在AR 42 J细胞中缺乏G α（16），这表明G α（14）可能在介导SSTR 2诱导的反应中起作用。通过在诱导时表达SSTR 2和G α的人胚肾293细胞中IKK和NF κ B的活化，进一步证实了G α的这种调节作用（14）。G β（1）γ（2）的刺激作用和过表达transducin的消除证实了G β γ参与SSTR 2介导的IKK/NF κ B激活。通过应用特异性抑制剂和显性失活突变体，磷脂酶C β、蛋白激酶C和钙调蛋白依赖性激酶II被证明参与SSTR 2诱导的反应。抑制c-Src和许多中间产物，包括Ras、Raf-1激酶、MEK 1/2，沿着细胞外信号调节激酶级联反应，可减弱生长抑素介导的IKK/NF κ B激活。虽然c-Jun N-末端激酶和p38丝裂原活化蛋白激酶（MAPK）也被SSTR 2刺激，但抑制这两种MAPK在改变生长抑素介导的反应方面是无效的。使用AR 42 J细胞也获得了类似的结果。这些数据表明，SSTR 2激活IKK/NF κ B信号级联需要一个由G α（14）和多种中间体组成的复杂网络。
Medications targeting the somatostatin type 2 receptor (SSTR2) have been employed for pancreatic inflammations and cancers, possibly via the regulation of the transcription factor nuclear factor kappa B (NF kappa B). Here we demonstrate that in tumoral pancreatic acinar AR42J cells, activation of SSTR2 leads to stimulation of the inhibitor kappa B kinase (IKK)/ NF kappa B signaling cascade via pertussis toxin-insensitive G proteins in a time- and dose-dependent manner. The inability of G(q/11) and G(12/13) proteins to activate IKK/NF kappa B by SSTR2 in transfected human embryonic kidney 293 cells and the lack of G alpha(16) in AR42J cells suggested a possible role of G alpha(14) in mediating SSTR2-induced responses. This regulatory role of G alpha(14) was further confirmed by the activation of IKK and NF kappa B in human embryonic kidney 293 cells expressing SSTR2 and G alpha(14) upon induction. The stimulatory effect of G beta(1)gamma(2) and the abrogation by overexpressing transducin confirmed the participation of G beta gamma in SSTR2-mediated IKK/NF kappa B activation. By the application of specific inhibitors and dominant negative mutants, phospholipase C beta, protein kinase C, and calmodulin-dependent kinase II were shown to be involved in SSTR2-induced responses. Inhibition of c-Src and numerous intermediates, including Ras, Raf-1 kinase, MEK1/2, along with the extracellular signal-regulated kinase cascade attenuated somatostatin-mediated IKK/NF kappa B activation. Although c-Jun N-terminal kinase and p38 mitogen-activated protein kinase ( MAPK) were also stimulated by SSTR2, suppression of these two MAPKs was ineffective in altering the somatostatin-mediated responses. Similar results were also obtained using AR42J cells. These data suggest that activation of the IKK/NF kappa B signaling cascade by SSTR2 requires a complicated network consisting of G alpha(14) and multiple intermediates.