Study summary · research use only
Gastrointestinal hormones/neurotransmitters and growth factors can activate P21 activated kinase 2 in pancreatic acinar cells by novel mechanisms
Plain-language summary
Paraphrased from the published abstract below — not a verdict on whether anything works.
In this study using rat pancreatic acini, the authors explored the ability of gastrointestinal hormones, neurotransmitters and growth factors to activate Group-I p-21-activated kinases (PAKs). The abstract reports that only PAK2 was present in acini and was activated by pancreatic growth factors (EGF, PDGF, bFGF), by secretagogues activating phospholipase-C (CCK, carbachol, bombesin), and by the PKC activator TPA, but not by agents only mobilizing calcium or raising cyclic AMP. It states CCK activation required both high- and low-affinity CCK1-receptor states, was partially reduced by PKC or Src inhibition but not PI3K inhibitors, and that IPA-3 partially inhibited PAK2 activation and reduced CCK-induced ERK1/2 activation and amylase release. The authors describe PAK2 as a potential therapeutic target in pancreatic disorders.
Abstract
P-21-activated kinases (PAKs) are serine/threonine kinases comprising six isoforms divided in two groups, group-I (PAK1-3)/group-II (PAK4-6) which play important roles in cell cytoskeletal dynamics, survival, secretion and proliferation and are activated by diverse stimuli. However, little is known about PAKs ability to be activated by gastrointestinal (GI) hormones/neurotransmitters/growth-factors. We used rat pancreatic acini to explore the ability of GI-hormones/neurotransmitters/growth-factors to activate Group-I-PAKs and the signaling cascades involved. Only PAK2 was present in acini. PAK2 was activated by some pancreatic growth-factors [EGF, PDGF, bFGF], by secretagogues activating phospholipase-C (PLC) [CCK, carbachol, bombesin] and by post-receptor stimulants activating PKC [TPA], but not agents only mobilizing cellular calcium or increasing cyclic AMP. CCK-activation of PAK2 required both high- and low-affinity-CCK1-receptor-state activation. It was partially reduced by PKC- or Src-inhibition, but not with PI3K-inhibitors (wortmannin, LY294002) or thapsigargin. IPA-3, which prevents PAK2 binding to small-GTPases partially inhibited PAK2-activation, as well as reduced CCK-induced ERK1/2 activation and amylase release induced by CCK or bombesin. This study demonstrates pancreatic acini, possess only one Group-I-PAK, PAK2. CCK and other GI-hormones/neurotransmitters/growth-factors activate PAK2 via small GTPases (CDC42/Rac1), PKC and SFK but not cytosolic calcium or PI3K. CCK-activation of PAK2 showed several novel features being dependent on both receptor-activation states, having PLC- and PKC-dependent/independent components and small-GTPase-dependent/independent components. These results show that PAK2 is important in signaling cascades activated by numerous pancreatic stimuli which mediate their various physiological/pathophysiological responses and thus could be a promising target for the development of therapies in some pancreatic disorders such as pancreatitis.
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