Protein Kinase Cμ Regulation of the JNK Pathway Is Triggered via Phosphoinositide-dependent Kinase 1 and Protein Kinase Cε

Brändlin, Ilona; Eiseler, Tim; Salowsky, Rüdiger; Johannes, Franz‐Josef

doi:10.1074/jbc.m205299200

Cited by 54 publications

(57 citation statements)

References 39 publications

(28 reference statements)

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“…PMA-mediated PKD Activation-PKD is activated in a PKCdependent fashion in some cell types (23)(24)(25)(26). To determine whether PKC isoforms are involved in PMA-induced PKD activation in BON cells, we examined the effect of three PKC inhibitors, Gö6983, GFX, and Ro31-8220, which inhibit activity of classic and novel PKC isoforms but not PKD (49,50) (Fig.…”

Section: Classic or Novel Pkc And Rho Kinase Inhibitors Attenuatementioning

confidence: 99%

mentioning

confidence: 99%

“…Expression of PKD has been demonstrated in some endocrine cells, including insulin-and gastrin-secreting cells (20 -22). PKD activation occurs through several mediators via a PKC-dependent pathway (23)(24)(25)(26).Recent studies indicate a close association between PKC isoforms and members of the Rho family of small GTP-binding proteins including Rho (A, B, and C), Rac1, and Cdc42 (27,28). The Rho family members, well-known regulators of the actin cytoskeleton and phosphoinositide metabolism (29), have been implicated in hormone secretion from endocrine cells (30 -32).…”

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confidence: 99%

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The Role of Protein Kinase D in Neurotensin Secretion Mediated by Protein Kinase C-α/-δ and Rho/Rho Kinase

O’Connor

Hellmich

et al. 2004

Journal of Biological Chemistry

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Neurotensin (NT) is a gut peptide that plays an important role in gastrointestinal (GI) secretion, motility, and growth as well as the proliferation of NT receptor positive cancers. Secretion of NT is regulated by phorbol ester-sensitive protein kinase C (PKC) isoforms-␣ and -␦ and may involve protein kinase D (PKD). The purpose of our present study was: (i) to define the role of PKD in NT release from BON endocrine cells and (ii) to delineate the upstream signaling mechanisms mediating this effect. Here, we demonstrate that small interfering RNA (siRNA) targeted against PKD dramatically inhibited both basal and PMA-stimulated NT secretion; NT release is significantly increased by overexpression of PKD. PKC-␣ and -␦ siRNA attenuated PKD activity, whereas overexpression of PKC-␣ and -␦ enhanced PKD activity. Rho kinase (ROK) siRNA significantly inhibited NT secretion, whereas overexpression of ROK␣ effectively increased NT release. Rho protein inhibitor C3 dramatically inhibited both NT secretion and PKD activity. In conclusion, our results demonstrate that PKD activation plays a central role in NT peptide secretion; upstream regulators of PKD include PKC-␣ and -␦ and Rho/ROK. Importantly, our results identify novel signaling pathways, which culminate in gut peptide release.Regulatory hormones, localized to specialized endocrine cells in the small bowel, control numerous physiological functions of the gastrointestinal (GI) tract including secretion, motility, and mucosal growth (1). The gut peptide neurotensin (NT), 1 a tridecapeptide localized to enteroendocrine cells (N cells) of the distal small bowel (2, 3), facilitates fatty acid translocation (4), affects gut motility (5), and stimulates growth of normal gut mucosa (6, 7). In addition to its trophic effects on normal GI tissues, NT stimulates proliferation of certain pancreatic, colonic, and prostatic cancers bearing NT receptors (NTR) (8). Although the mechanisms for pancreatic hormone release have been well characterized (9), the signal transduction pathways regulating stimuli-induced gut hormone secretion are not entirely understood. One reason for this paucity in our understanding is the relative lack of useful in vitro models that recapitulate in vivo properties of intestinal endocrine cells.The BON endocrine cell line was established from a human pancreatic carcinoid tumor and characterized in our laboratory (10). These cells have served as an invaluable in vitro model for hormone secretion studies. Similar to the terminally differentiated N cell of the small bowel, BON cells express high levels of NT/neuromedin N mRNA, synthesize and secrete NT peptide, and process the NT/neuromedin N precursor protein in a fashion identical to that of the normal intestine (11). BON cells exhibit morphological and biochemical characteristics consistent with the enteroendocrine cell phenotype, including the presence of numerous dense core granules and the expression and secretion of chromogranin A and other peptides (e.g. pancreastatin) (10, 12, 13). Thus, the BON cel...

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Section: Classic or Novel Pkc And Rho Kinase Inhibitors Attenuatementioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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The Role of Protein Kinase D in Neurotensin Secretion Mediated by Protein Kinase C-α/-δ and Rho/Rho Kinase

O’Connor

Hellmich

et al. 2004

Journal of Biological Chemistry

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“…PKCm has been shown to participate in the control of keratinocyte proliferation (Rennecke et al, 1999) to counteract TNF-induced apoptosis in HeLa cells (Johannes et al, 1998), and is probably involved in the function of invadopodia formed by breast cancer cells during invasion of the surrounding tissues (Bowden et al, 1999). Particularly in the context of breast cancer, PKCm and its upstream activating kinase PKCe seemed to be involved in triggering cellular adhesion processes (Platet et al, 1998;Palmantier et al, 2001;Brandlin et al, 2002).…”

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confidence: 99%

PKCμ prevents CD95-mediated apoptosis and enhances proliferation in pancreatic tumour cells

et al. 2003

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“…They share similar structural features and often phosphorylate the same substrates (1)(2)(3)(4)(5)(6)(7). The protein kinase D family has been implicated in the regulation of proliferation of different cells including pancreatic cancer cells (6 -11).…”

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confidence: 99%

Protein Kinase D1 Mediates Anchorage-dependent and -independent Growth of Tumor Cells via the Zinc Finger Transcription Factor Snail1

Eiseler

Köhler

Nimmagadda

et al. 2012

Journal of Biological Chemistry

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Background:The protein kinase D (PKD) family is involved in the control of cell motility and proliferation. Results: PKD1 controls growth of cancer cells through phosphorylation of Snail1 at Ser-11. Conclusion: Only PKD1, but not PKD2, mediates isoform-specific control of pancreatic cancer cell proliferation through Snail1. Significance: We demonstrate for the first time isoform-specific control of pancreatic cancer growth by a single phosphorylation of a substrate.

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Protein Kinase Cμ Regulation of the JNK Pathway Is Triggered via Phosphoinositide-dependent Kinase 1 and Protein Kinase Cε

Cited by 54 publications

References 39 publications

The Role of Protein Kinase D in Neurotensin Secretion Mediated by Protein Kinase C-α/-δ and Rho/Rho Kinase

The Role of Protein Kinase D in Neurotensin Secretion Mediated by Protein Kinase C-α/-δ and Rho/Rho Kinase

PKCμ prevents CD95-mediated apoptosis and enhances proliferation in pancreatic tumour cells

Protein Kinase D1 Mediates Anchorage-dependent and -independent Growth of Tumor Cells via the Zinc Finger Transcription Factor Snail1

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