PKD3 Is the Predominant Protein Kinase D Isoform in Mouse Exocrine Pancreas and Promotes Hormone-induced Amylase Secretion

Chen, L. Andy; Li, Jing; Silva, Scott R.; Jackson, Lindsey N.; Zhou, Yifeng; Watanabe, Hiroaki; Ives, Kirk L.; Hellmich, Mark R.; Evers, B. Mark

doi:10.1074/jbc.m801697200

Cited by 29 publications

(25 citation statements)

References 72 publications

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“…In melanoma cells, PRKD2 protein expression was undetectable and thus it was not tested in our sensitization studies. Even though PRKD members share some cellular functions, they can be differentially expressed and exert different functions (28). Further investigation of PRKD3 specific cellular function(s) will be required to better understand how PRKD3 ablation augments RAF265 activity in melanoma.…”

Section: Discussionmentioning

confidence: 99%

“…Similar to PRKD1 and PRKD2, PRKD3 has been shown to function in protein trafficking and as a histone deacetylase kinase (26,27). One report showed that PRKD3 enhanced CCK-mediated pancreatic amylase secretion via MEK-ERK-RSK signaling and this process was activated by GI hormone (28). Another report showed that PRKD3 expression levels were elevated in human prostate cancers compared with normal tissues; PRKD3 overexpression activated AKT and ERK in prostate cancer cell lines and promoted cell growth and survival (29).…”

Section: Introductionmentioning

confidence: 99%

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Protein Kinase D3 Sensitizes RAF Inhibitor RAF265 in Melanoma Cells by Preventing Reactivation of MAPK Signaling

et al. 2011

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RAS mutations occur in more than 30% of all human cancers but efforts to directly target mutant RAS signaling as a cancer therapy have yet to succeed. As alternative strategies, RAF and MEK inhibitors have been developed to block oncogenic signaling downstream of RAS. As might be expected, studies of these inhibitors have indicated that tumors with RAS or BRAF mutations display resistance RAF or MEK inhibitors. In order to better understand the mechanistic basis for this resistance, we conducted a RNAi-based screen to identify genes that mediated chemoresistance to the RAF kinase inhibitor RAF265 in a BRAF (V600E) mutant melanoma cell line that is resistant to this drug. In this way, we found that knockdown of protein kinase D3 (PRKD3) could enhance cell killing of RAF and MEK inhibitors across multiple melanoma cell lines of various genotypes and sensitivities to RAF265. PRKD3 blockade cooperated with RAF265 to prevent reactivation of the MAPK signaling pathway, interrupt cell cycle progression, trigger apoptosis, and inhibit colony formation growth. Our findings offer initial proof-of-concept that PRKD3 is a valid target to overcome drug resistance being encountered widely in the clinic with RAF or MEK inhibitors. Cancer Res; 71(12); 4280-91. Ó2011 AACR.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Protein Kinase D3 Sensitizes RAF Inhibitor RAF265 in Melanoma Cells by Preventing Reactivation of MAPK Signaling

et al. 2011

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“…Recently, our group and others explored the regulation of PKD isoforms in the major cells of exocrine pancreas, i.e., pancreatic acinar cells, from rats and mice [16, 17, 33, 34]. The studies showed that PKD/PKD1, the major PKD isoform in rat pancreatic acinar cells, is activated by phorbol esters and multiple pancreatic secretagogues, including cholecystokinin-8 (CCK-8 or CCK), the cholinergic agonist carbachol (CCh), and bombesin, but not by growth factors [16, 17, 33, 34].…”

Section: Pkd Structure and Regulation In Pancreatic Acinar Cellsmentioning

confidence: 99%

“…The studies showed that PKD/PKD1, the major PKD isoform in rat pancreatic acinar cells, is activated by phorbol esters and multiple pancreatic secretagogues, including cholecystokinin-8 (CCK-8 or CCK), the cholinergic agonist carbachol (CCh), and bombesin, but not by growth factors [16, 17, 33, 34]. In isolated rat pancreatic acinar cells, CCK and CCh induced a dose-dependent rapid activation of PKD as measured by an in vitro kinase assay and by phosphorylation at the activation loop (Ser-744/748) or autophosphorylation site (Ser-916) [16, 17, 33].…”

Section: Pkd Structure and Regulation In Pancreatic Acinar Cellsmentioning

confidence: 99%

PKD signaling and pancreatitis

Yuan

Pandol

2016

J Gastroenterol

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Background Acute pancreatitis is a serious medical disorder with no current therapies directed to the molecular pathogenesis of the disorder. Inflammation, inappropriate intracellular activation of digestive enzymes, and parenchymal acinar cell death by necrosis are the critical pathophysiologic processes of acute pancreatitis. Thus, it is necessary to elucidate the key molecular signals that mediate these pathobiologic processes and develop new therapeutic strategies to attenuate the appropriate signaling pathways in order to improve outcomes for this disease. A novel serine/threonine protein kinase D (PKD) family has emerged as key participants in signal transduction, and this family is increasingly being implicated in the regulation of multiple cellular functions and diseases. Methods This review summarizes recent findings of our group and others regarding the signaling pathway and the biological roles of the PKD family in pancreatic acinar cells. In particular, we highlight our studies of the functions of PKD in several key pathobiologic processes associated with acute pancreatitis in experimental models. Results Our findings reveal that PKD signaling is required for NF-κB activation/inflammation, intracellular zymogen activation, and acinar cell necrosis in rodent experimental pancreatitis. Novel small-molecule PKD inhibitors attenuate the severity of pancreatitis in both in vitro and in vivo experimental models. Further, this review emphasizes our latest advances in the therapeutic application of PKD inhibitors to experimental pancreatitis after the initiation of pancreatitis. Conclusions These novel findings suggest that PKD signaling is a necessary modulator in key initiating pathobiologic processes of pancreatitis, and that it constitutes a novel therapeutic target for treatments of this disorder.

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“…Three members of the PKD family have been identified to date, namely, PKD1 (PKCm), PKD2 and PKD3 (PKCn) (Wang, 2006). PKD has been implicated in various biological processes, such as cell proliferation (McEneaney et al, 2010;Papazyan et al, 2008;Wang, 2006), survival (Arun et al, 2011;Song et al, 2009), cell migration (Eiseler et al, 2010;Peterburs et al, 2009), differentiation (Jadali and Ghazizadeh, 2010;Kleger et al, 2011), inflammation (Kim et al, 2010b;Park et al, 2009) and vesicle transportation (Chen et al, 2009;Hausser et al, 2005;Lu et al, 2007). The role of PKDs in cancer invasion/metastasis has been increasingly recognized, and, of the three PKD isoforms, PKD1 has been the focus of most studies in this context.…”

Section: Introductionmentioning

confidence: 99%

PKD2 and PKD3 Promote Prostate Cancer Cell Invasion via uPA by Shifting Balance Between NF-κB and HDAC1

Zou

Zeng

et al. 2012

Journal of Cell Science

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SummaryAlthough protein kinase D3 (PKD3) has been shown to contribute to prostate cancer cell growth and survival, the role of PKD in prostate cancer cell motility remains unclear. Here, we show that PKD2 and PKD3 promote nuclear factor kappa B (NF-kB) signaling and urokinase-type plasminogen activator (uPA) expression/activation, which are crucial for prostate cancer cell invasion. Silencing of endogenous PKD2 and/or PKD3 markedly decreased prostate cancer cell migration and invasion, reduced uPA and uPA receptor (uPAR) expression and increased plasminogen activator inhibitor-2 (PAI-2) expression. These results were further substantiated by the finding that PKD2 and PKD3 promoted the activity of uPA and matrix metalloproteinase 9 (MMP9). Furthermore, depletion of PKD2 and/or PKD3 decreased the level of binding of the p65 subunit of NF-kB to the promoter of the gene encoding uPA (PLAU), suppressing transcriptional activation of uPA. Endogenous PKD2 and PKD3 interacted with inhibitor of NF-kB (IkB) kinase b (IKKb); PKD2 mainly regulated the phosphorylated IKK (pIKK)-phosphorylated IkB (pIkB)-IkB degradation cascade, p65 nuclear translocation, and phosphorylation of Ser276 on p65, whereas PKD3 was responsible for the phosphorylation of Ser536 on p65. Conversely, inhibition of uPA transactivation by PKD3 silencing was rescued by constitutive Ser536 p65 phosphorylation, and reduced tumor cell invasion resulting from PKD2 or PKD3 silencing was rescued by ectopic expression of p65. Interestingly, PKD3 interacted with histone deacetylase 1 (HDAC1), suppressing HDAC1 expression and decreasing its binding to the uPA promoter. Moreover, depletion of HDAC1 resulted in recovery of uPA transactivation in PKD3-knockdown cells. Taken together, these data suggest that PKD2 and PKD3 coordinate to promote prostate cancer cell invasion through p65 NF-kB-and HDAC1-mediated expression and activation of uPA.

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PKD3 Is the Predominant Protein Kinase D Isoform in Mouse Exocrine Pancreas and Promotes Hormone-induced Amylase Secretion

Cited by 29 publications

References 72 publications

Protein Kinase D3 Sensitizes RAF Inhibitor RAF265 in Melanoma Cells by Preventing Reactivation of MAPK Signaling

Protein Kinase D3 Sensitizes RAF Inhibitor RAF265 in Melanoma Cells by Preventing Reactivation of MAPK Signaling

PKD signaling and pancreatitis

PKD2 and PKD3 Promote Prostate Cancer Cell Invasion via uPA by Shifting Balance Between NF-κB and HDAC1

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