The p21-activated kinase, PAK2, is important in the activation of numerous pancreatic acinar cell signaling cascades and in the onset of early pancreatitis events.
The p21-activated kinase, PAK2, is important in the activation of numerous pancreatic acinar cell signaling cascades and in the onset of early pancreatitis events.
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DOI：
10.1016/j.bbadis.2016.02.008
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发表时间：
2016-06
期刊：
影响因子：
--
通讯作者：
Jensen RT
中科院分区：
文献类型：
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作者：
Nuche-Berenguer B;Ramos-Álvarez I;Jensen RT
在最近的一项研究中，我们探讨了group -1-p21活化激酶（GP）。1-PAKs)在大鼠胰腺腺泡中的表达。只有PAK2存在；它被胃肠道激素/神经递质和生长因子以PKC、Src和小gtpases介导的方式激活。PAK2是酶分泌和ERK/1-2活化所必需的。在本研究中，我们研究了PAK2在CCK和tpa的重要远端信号级联激活中介导其生理/病理生理效应的作用，并分析了其在早期胰腺炎重要病理生理过程中的作用。在大鼠胰腺腺泡中，pak2被特异性的GP.1抑制。帕克抑制剂，ipa -3抑制胆囊收缩素(CCK)/ tpa刺激局灶黏附激酶和丝裂原活化蛋白激酶的激活。pak2抑制逆转了CCK/TPA对PI3K/Akt/GSK-3β通路的双重刺激/抑制作用。然而，它的抑制作用并不影响PKC的激活。pak2抑制可保护腺泡细胞免受cck诱导的ros生成；半胱天冬酶/胰蛋白酶活化在早期胰腺炎中很重要；以及细胞坏死。此外，pak2抑制降低了参与程序性细胞死亡的PAK-2p34的蛋白水解活化。为了确保这项研究不仅仅依赖于IPA-3作为PAK抑制剂的特异性，我们使用了另外两种方法来抑制PAK，即FRAX597 a atp竞争性gp。1-PAKs -抑制剂和pak2显性阴性(DN)- advirus感染。这两种方法证实了IPA-3的结果。该研究表明，PAK2在介导CCK对已知介导其生理/病理生理反应的信号通路激活的作用中发挥重要作用，包括与胰腺炎发病相关的几个细胞过程。我们的研究结果表明，PAK2可能是一个新的、重要的治疗靶点，可以考虑治疗涉及胰腺腺泡细胞失调的疾病。
In a recent study we explored Group-1-p21-activated kinases(GP.1-PAKs) in rat pancreatic acini. Only PAK2 was present; it was activated by gastrointestinal-hormones/neurotransmitters and growth factors in a PKC-,Src- and small-GTPases-mediated manner. PAK2 was required for enzyme-secretion and ERK/1-2-activation. In the present study we examined PAK2’s role in CCK and TPA-activation of important distal signaling cascades mediating their physiological/pathophysiological effects and analyzed its role in pathophysiological processes important in early pancreatitis. In rat pancreatic acini,PAK2-inhibition by the specific, GP.1.PAK-inhibitor, IPA-3-suppressed cholecystokinin(CCK)/TPA-stimulated activation of focal-adhesion kinases and mitogen-activated protein-kinases. PAK2-inhibition reversed the dual stimulatory/inhibitory effect of CCK/TPA on the PI3K/Akt/GSK-3β pathway. However, its inhibition did not affect PKC activation. PAK2-inhibition protected acini from CCK-induced ROS-generation; caspase/trypsin-activation, important in early pancreatitis; as well as from cell-necrosis. Furthermore, PAK2-inhibition reduced proteolytic-activation of PAK-2p34, which is involved in programmed-cell-death. To ensure that the study did not only rely in the specificity of IPA-3 as a PAK inhibitor, we used two other approaches for PAK inhibition, FRAX597 a ATP-competitive-GP.1-PAKs - inhibitor and by infection with an PAK2-dominat negative(DN)-Advirus. Those two approaches confirmed the results obtained with IPA-3. This study demonstrates that PAK2 is important in mediating CCK’s effect on the activation of signaling-pathways known to mediate its physiological/pathophysiological responses including several cellular processes linked to the onset of pancreatitis. Our results suggest that PAK2 could be a new, important therapeutic target to consider for the treatment of diseases involving deregulation of pancreatic acinar cells.