p-21 activated kinase 4 promotes proliferation and survival of pancreatic cancer cells through AKT- and ERK-dependent activation of NF-κB pathway

Tyagi, Nidhi; Bhardwaj, Arun; Singh, Ajay P.; McClellan, Steven; Carter, James E.; Singh, Seema

doi:10.18632/oncotarget.2398

Cited by 108 publications

(114 citation statements)

References 42 publications

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“…Gene amplification has been most frequently observed for PAK4, specifically in pancreatic, ovarian, and colon cancers (65,(77)(78)(79) as well as multiple tumor cell lines (6,76,80). Amplifications of PAK5 in colorectal (81,82) and PAK6 in prostate cancer (83) have also been observed.…”

Section: Alteration Of Type II Pak Signaling In Cancermentioning

confidence: 99%

Signaling, Regulation, and Specificity of the Type II p21-activated Kinases

Ha¹,

Morse

Turk³

et al. 2015

Journal of Biological Chemistry

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The p21-activated kinases (PAKs) are a family of six serine/ threonine kinases that act as key effectors of RHO family GTPases in mammalian cells. PAKs are subdivided into two groups: type I PAKs (PAK1, PAK2, and PAK3) and type II PAKs (PAK4, PAK5, and PAK6). Although these groups are involved in common signaling pathways, recent work indicates that the two groups have distinct modes of regulation and have both unique and common substrates. Here, we review recent insights into the molecular level details that govern regulation of type II PAK signaling. We also consider mechanisms by which signal transduction is regulated at the level of substrate specificity. Finally, we discuss the implications of these studies for clinical targeting of these kinases.The type II PAKs 2 are members of the Sterile 20 (Ste20) family of STE (homologs of yeast Sterile 7, Sterile 11, and Sterile 20) group serine/threonine kinases. They are important for signaling from small GTPases of the RHO family, particularly the CDC42 (cell division cycle 42) and to a lesser extent RAC (Rasrelated C3 botulinum toxin substrate) isoforms, to the actin cytoskeleton and to growth and survival pathways. Type II PAKs share significant sequence similarity with the well studied type I PAKs (PAK1, PAK2, and PAK3), which are extensively reviewed elsewhere (1-5), but the roles of the type I and type II PAKs in GTPase signaling pathways, and their mechanisms of regulation, differ considerably. In the sections below, we consider the function of the type II PAK serine/threonine kinases in small GTPase pathways, the structural and biochemical basis for their regulation, mechanisms of their targeting to substrates, and some of the current strategies for targeted small molecule inhibition of these enzymes. Type II PAKs in Signal TransductionThe type II PAKs are binding partners of RHO family small GTPases. Their dominant role in signal transduction is as serine/threonine kinases, where transfer of the ␥-phosphate from an ATP molecule to a substrate protein results in consequent regulation of downstream effector pathways. The activation of type II PAK kinase signaling is associated with small GTPase binding, but as discussed below, direct activation does not seem to occur upon small GTPase binding. Rather, GTPases are thought to primarily regulate type II PAKs by controlling their subcellular localization. Type II PAKs also have reported kinase-independent roles as scaffolding proteins, with functions that are still emerging.The type II PAKs are placed at critical nodal points in multiple signaling pathways that are associated with cell growth, cytoskeletal dynamics, cell polarity, survival, and development (6 -8). They are located directly downstream of RHO family GTPase activation. Numerous substrates of type II PAKs have been identified that are thought to act as downstream effectors in distinct cellular processes. For example, direct phosphorylation of LIM kinases (9, 10), p210/␤-catenin (11, 12), slingshot phosphatase (SSH) (13), 14), and PDZ-RHOGEF (15) has...

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Section: Alteration Of Type II Pak Signaling In Cancermentioning

confidence: 99%

Signaling, Regulation, and Specificity of the Type II p21-activated Kinases

Ha¹,

Morse

Turk³

et al. 2015

Journal of Biological Chemistry

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“…ERK1 and ERK2 are two important family members, and the signal transduction pathways in which they are involved are closely associated with the occurrence and development of tumors (7). Furthermore, Tyagi et al (8) indicated that P-21 activated kinase 4 promotes the proliferation and survival of pancreatic cancer cells via the ERK pathway. In addition, Li et al (9) reported that hyperglycemia regulates the thioredoxin-interacting protein/ thioredoxin/reactive oxygen species axis of pancreatic cancer via the p38 MAPK and ERK pathways.…”

Section: Introductionmentioning

confidence: 99%

Paeoniflorin inhibits human pancreatic cancer cell apoptosis via suppression of MMP-9 and ERK signaling

et al. 2016

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Abstract. Paeoniflorin exhibits anticancer, anti-inflammatory and antioxidation effects, as well as specific pharmacological effects on smooth muscle and the immune, cardiovascular and central nervous systems. The present study aimed to investigate the anticancer effects of paeoniflorin on pancreatic cancer cells and to elucidate the mechanisms by which these effects occur. In the present study, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and lactate dehydrogenase assays were performed to assess cell viability and cell cytotoxicity of BXPC-3 human pancreatic cancer cells, respectively. Cellular apoptosis and caspase-3/9 activities were analyzed using an Annexin V-fluorescein isothiocyanate/propidium iodide Apoptosis Detection kit, a DAPI staining assay and colorimetric kits, respectively. Matrix metalloproteinase-9 (MMP-9) and extracellular signal-regulated kinases (ERK) protein expression in BXPC-3 cells were also investigated using gelatin zymography assays and western blot analysis, respectively. In the present study, paeoniflorin was found to inhibit the cell viability and increase cell cytotoxicity of BXPC-3 cells in a dose-and time-dependent manner. In addition, cellular apoptosis, as well as caspase-3 and -9 activity of BXPC-3 cells was increased following paeoniflorin treatment. Notably, paeoniflorin reduced MMP-9 and ERK protein expression in BXPC-3 cells. These results indicate that paeoniflorin exhibits a potential anticancer effect by enhancing human pancreatic cancer cell apoptosis via the suppression of MMP-9 and ERK signaling.

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“…The PI3K/PTEN/Akt/mTORC1 and Raf/MEK/ERK are key pathways activated in pancreatic cancer, in part due to the frequent KRAS mutation (Tyagi et al, 2014). Targeting PI3K and other molecules in this pathway may be a therapeutic approach to treat pancreatic and other cancers (Chiarini et al, 2015).…”

Section: The Pi3k/pten/akt/mtorc1/gsk-3 and Raf/mek/erk Pathways In Pmentioning

confidence: 99%

Roles of EGFR and KRAS and their downstream signaling pathways in pancreatic cancer and pancreatic cancer stem cells

Fitzgerald

Lertpiriyapong

Cocco

et al. 2015

Advances in Biological Regulation

129

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p-21 activated kinase 4 promotes proliferation and survival of pancreatic cancer cells through AKT- and ERK-dependent activation of NF-κB pathway

Cited by 108 publications

References 42 publications

Signaling, Regulation, and Specificity of the Type II p21-activated Kinases

Signaling, Regulation, and Specificity of the Type II p21-activated Kinases

Paeoniflorin inhibits human pancreatic cancer cell apoptosis via suppression of MMP-9 and ERK signaling

Roles of EGFR and KRAS and their downstream signaling pathways in pancreatic cancer and pancreatic cancer stem cells

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