PAK family kinases

Zhao, Zhuoshen; Manser, Ed

doi:10.4161/cl.21912

Cited by 97 publications

(67 citation statements)

References 126 publications

(179 reference statements)

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“…S3A). While Thr423/402 residues in the catalytic kinase domain and Ser199/204/ Ser192/197 adjacent to auto-inhibitory domain (AID) are targeted by other regulatory molecules in a GTPase-independent manner (42, 43). For example, S-ketorolac may inhibit phosphorylation on these sites by affecting lipid-dependent stimulation of PAK1/PAK2 (e.g.…”

Section: Resultsmentioning

confidence: 99%

R-Ketorolac Targets Cdc42 and Rac1 and Alters Ovarian Cancer Cell Behaviors Critical for Invasion and Metastasis

Guo

Kenney

Muller

et al. 2015

Molecular Cancer Therapeutics

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Cdc42 (cell division control protein 42) and Rac1 (Ras-related C3 botulinum toxin substrate 1) are attractive therapeutic targets in ovarian cancer based on established importance in tumor cell migration, adhesion and invasion. Despite a predicted benefit, targeting GTPases has not yet been translated to clinical practice. We previously established that Cdc42 and constitutively active Rac1b are overexpressed in primary ovarian tumor tissues. Through high throughput screening and computational shape homology approaches we identified R-ketorolac as a Cdc42 and Rac1 inhibitor; distinct from the anti-inflammatory, cyclooxygenase inhibitory activity of S-ketorolac. In the present study, we establish R-ketorolac as an allosteric inhibitor of Cdc42 and Rac1. Cell-based assays validate R-ketorolac activity against Cdc42 and Rac1. Studies on immortalized human ovarian adenocarcinoma cells (SKOV3ip), and primary, patient-derived ovarian cancer cells show R-ketorolac is a robust inhibitor of growth factor or serum dependent Cdc42 and Rac1 activation with a potency and cellular efficacy similar to small molecule inhibitors of Cdc42 (CID2950007/ML141) and Rac1 (NSC23766). Furthermore, GTPase inhibition by R-ketorolac reduces downstream p21-activated kinases (PAK1/PAK2) effector activation by >80%. Multiple assays of cell behavior using SKOV3ip and primary patient-derived ovarian cancer cells show that R-ketorolac significantly inhibits cell adhesion, migration and invasion. In sum, we provide evidence for R-ketorolac as direct inhibitor of Cdc42 and Rac1 that is capable of modulating downstream GTPase-dependent, physiological responses, which are critical to tumor metastasis. Our findings demonstrate the selective inhibition of Cdc42 and Rac1 GTPases by an FDA approved drug-racemic ketorolac that can be used in humans.

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Section: Resultsmentioning

confidence: 99%

R-Ketorolac Targets Cdc42 and Rac1 and Alters Ovarian Cancer Cell Behaviors Critical for Invasion and Metastasis

Guo

Kenney

Muller

et al. 2015

Molecular Cancer Therapeutics

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“…Group I PAKs are the most extensively studied and in several cell types, are reported to be important for regulating and modulating signaling cascades involved in cytoskeletal organization, cell proliferation, tumorigenic processes, migration and apoptosis, protein synthesis and to play an important role in secretion, membrane recycling, generation of reactive oxygen species, apoptosis and regulation of cellular calcium levels [1,3-9]. PAK signaling roles in cell cycle regulation, neoplastic processes and inflammation have been extensively studied [2,4], as has been their activation by growth factors and growth stimulants [2,4,8]. However, increasingly, PAKs are reported to be involved in non-neoplastic responses of cells as well as responses of normal tissues.…”

Section: Introductionmentioning

confidence: 99%

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

Nuche-Berenguer

Ramos-Álvarez

Jensen

2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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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.

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“…The PAK family consists of six members that are segregated into two subgroups (Group I and Group II) based on sequence homology [1,3–6]. Group-I-PAKs (PAK 1–3) are the most extensively studied and play an important role in signaling for many cellular processes, such as regulation of cell survival, apoptosis, cell motility, tumorigenesis, protein synthesis, glucose homeostasis, secretion and cellular proliferation [1–5,7–14]. The Group-I-PAKs normal tissue expression varies greatly between the three isoforms [15,16].…”

Section: Introductionmentioning

confidence: 99%

Gastrointestinal hormones/neurotransmitters and growth factors can activate P21 activated kinase 2 in pancreatic acinar cells by novel mechanisms

Nuche-Berenguer

Jensen

2015

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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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 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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PAK family kinases

Cited by 97 publications

References 126 publications

R-Ketorolac Targets Cdc42 and Rac1 and Alters Ovarian Cancer Cell Behaviors Critical for Invasion and Metastasis

R-Ketorolac Targets Cdc42 and Rac1 and Alters Ovarian Cancer Cell Behaviors Critical for Invasion and Metastasis

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

Gastrointestinal hormones/neurotransmitters and growth factors can activate P21 activated kinase 2 in pancreatic acinar cells by novel mechanisms

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