Protein kinase D2 regulates chromogranin A secretion in human BON neuroendocrine tumour cells

Wichert, Götz von; Edenfeld, Teresa; Blume, Julia von; Krisp, Holger; Krndija, Denis; Schmid, Heidrun; Oswald, Franz; Lother, Ulrike; Walther, Paul; Adler, Guido; Seufferlein, Thomas

doi:10.1016/j.cellsig.2008.01.003

Cited by 21 publications

(15 citation statements)

References 16 publications

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“…Although all PKDs are regulated by a DAG-binding C1 domain and by an activation loop, they have been shown to regulate secretion of different cargo molecules. For instance, PKD1 has been involved in secretion of matrix metalloproteinase-2 and -9 from prostate cancer cells [61] or of insulin [62]; PKD2 was shown to regulate hypoxia-induced VEGF-A secretion from pancreatic tumor cells [63] or secretion of chromogranin A from neuroendocrine tumor cells [64]; and PKD3 promoted secretion of cholecystokinin-mediated pancreatic amylase [65]. On the other hand, none of the PKDs has ever been linked to the release of antimicrobial peptides and/or regulation of infections, thus our studies are novel.…”

Section: Discussionmentioning

confidence: 99%

Role of Sphingomyelin Synthase in Controlling the Antimicrobial Activity of Neutrophils against Cryptococcus neoformans

et al. 2010

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The key host cellular pathway(s) necessary to control the infection caused by inhalation of the environmental fungal pathogen Cryptococcus neoformans are still largely unknown. Here we have identified that the sphingolipid pathway in neutrophils is required for them to exert their killing activity on the fungus. In particular, using both pharmacological and genetic approaches, we show that inhibition of sphingomyelin synthase (SMS) activity profoundly impairs the killing ability of neutrophils by preventing the extracellular release of an antifungal factor(s). We next found that inhibition of protein kinase D (PKD), which controls vesicular sorting and secretion and is regulated by diacylglycerol (DAG) produced by SMS, totally blocks the extracellular killing activity of neutrophils against C. neoformans. The expression of SMS genes, SMS activity and the levels of the lipids regulated by SMS (namely sphingomyelin (SM) and DAG) are up-regulated during neutrophil differentiation. Finally, tissue imaging of lungs infected with C. neoformans using matrix-assisted laser desorption-ionization mass spectrometry (MALDI-MS), revealed that specific SM species are associated with neutrophil infiltration at the site of the infection. This study establishes a key role for SMS in the regulation of the killing activity of neutrophils against C. neoformans through a DAG-PKD dependent mechanism, and provides, for the first time, new insights into the protective role of host sphingolipids against a fungal infection.

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Section: Discussionmentioning

confidence: 99%

Role of Sphingomyelin Synthase in Controlling the Antimicrobial Activity of Neutrophils against Cryptococcus neoformans

et al. 2010

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“…Interestingly, a number of reports have demonstrated a requirement for PKD in diverse processes that rely on TGN-to-PM protein transport. PKD has been implicated in regulating the secretion of several important molecules, including insulin (61)(62)(63)(64). In neurons, PKD has been shown to regulate Golgi-dependent trafficking of dendritic membrane proteins (65), neuronal polarity (66), and dendritic arborization (67).…”

Section: Discussionmentioning

confidence: 99%

Regulation of Constitutive Cargo Transport from the trans-Golgi Network to Plasma Membrane by Golgi-localized G Protein βγ Subunits

Irannejad

Wedegaertner

2010

Journal of Biological Chemistry

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Observations of Golgi fragmentation upon introduction of G protein ␤␥ (G␤␥) subunits into cells have implicated G␤␥ in a pathway controlling the fission at the trans-Golgi network (TGN) of plasma membrane (PM)-destined transport carriers. However, the subcellular location where G␤␥ acts to provoke Golgi fragmentation is not known. Additionally, a role for G␤␥ in regulating TGN-to-PM transport has not been demonstrated. Here we report that constitutive or inducible targeting of G␤␥ to the Golgi, but not other subcellular locations, causes phospholipase C-and protein kinase D-dependent vesiculation of the Golgi in HeLa cells; Golgi-targeted ␤ 1 ␥ 2 also activates protein kinase D. Moreover, the novel G␤␥ inhibitor, gallein, and the G␤␥-sequestering protein, GRK2ct, reveal that G␤␥ is required for the constitutive PM transport of two model cargo proteins, VSV-G and ss-HRP. Importantly, Golgi-targeted GRK2ct, but not a PM-targeted GRK2ct, also blocks protein transport to the PM. To further support a role for Golgi-localized G␤␥, endogenous G␤ was detected at the Golgi in HeLa cells. These results are the first to establish a role for Golgi-localized G␤␥ in regulating protein transport from the TGN to the cell surface.Heterotrimeric G proteins, composed of ␣, ␤, and ␥ subunits, are involved in a wide variety of signaling responses and act by coupling heptahelical G protein-coupled receptors (GPCRs) 2 to intracellular effector proteins. In its inactive state, the G␣ subunit is bound to GDP and is also tightly bound to the G␤␥ subunits. Upon receptor activation by ligand binding, the GPCR catalyzes the exchange of GDP for GTP on the G␣, resulting in dissociation of G␣ and G␤␥. The separated subunits are then able to elicit their own signaling cascades. Hydrolysis of GTP by G␣, followed by re-association of G␣ and G␤␥, completes the cycle (1, 2).

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“…Interestingly, the PKD/Kidins220 pathway appears to function downstream of PKD-induced fission of TGN carriers, suggesting that PKD regulates different steps of cell secretion. In addition to PKD, PKD2 has been shown to regulate chromogranin release in BON cells [87]. Other studies indicate that PKDs play a critical role in regulating angiotensin II-mediated cortisol and aldosterone secretion from H295R cells, a human adrenocortical cell line [88, 89].…”

Section: Biological Role Of Pkd Family In Neoplasiamentioning

confidence: 99%

Role of protein kinase D signaling in pancreatic cancer

Guha

Tanasanvimon

Sinnett‐Smith

2010

Biochemical Pharmacology

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Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with dismal survival rates. Its intransigence to conventional therapy renders PDAC an aggressive disease with early metastatic potential. Thus, novel targets for PDAC therapy are urgently needed. Multiple signal transduction pathways are implicated in progression of PDAC. These pathways stimulate production of intracellular messengers in their target cells to modify their behavior, including the lipid-derived diacylglycerol (DAG). One of the prominent intracellular targets of DAG is the protein kinase C (PKC) family. However, the mechanisms by which PKC-mediated signals are decoded by the cell remain incompletely understood. Protein kinase D1 (PKD or PKD1, initially called atypical PKCµ), is the founding member of a novel protein kinase family that includes two additional protein kinases that share extensive overall homology with PKD, termed PKD2, and PKD3. The PKD family occupies a unique position in the signal transduction pathways initiated by DAG and PKC. PKD lies downstream of PKCs in a novel signal transduction pathway implicated in the regulation of multiple fundamental biological processes. We and others have shown that PKD-mediated signaling pathways promote mitogenesis and angiogenesis in PDAC. Our recent observations demonstrate that PKD also potentiates chemoresistance and invasive potential of PDAC cells. This review will briefly highlight diverse biological roles of PKD family in multiple neoplasias including PDAC. Further, this review will underscore our latest advancement with the development of a potent PKD family inhibitor and its effect both in vitro and in vivo in PDAC.

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Protein kinase D2 regulates chromogranin A secretion in human BON neuroendocrine tumour cells

Cited by 21 publications

References 16 publications

Role of Sphingomyelin Synthase in Controlling the Antimicrobial Activity of Neutrophils against Cryptococcus neoformans

Role of Sphingomyelin Synthase in Controlling the Antimicrobial Activity of Neutrophils against Cryptococcus neoformans

Regulation of Constitutive Cargo Transport from the trans-Golgi Network to Plasma Membrane by Golgi-localized G Protein βγ Subunits

Role of protein kinase D signaling in pancreatic cancer

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