Cross-talk between Protein Kinases Cζ and B in Cyclic AMP-mediated Sodium Taurocholate Co-transporting Polypeptide Translocation in Hepatocytes

McConkey, Marie; Gillin, Henry; Webster, Cynthia R. L.; Anwer, M. Sawkat

doi:10.1074/jbc.m309988200

Cited by 59 publications

(54 citation statements)

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“…We thus focused on PKC, which has been recently implicated in cAMPinduced signaling. 44,45 We found that an increase in cellular cAMP level had a major effect on PKC activity. As shown in Figure 2A, 24-hour treatment of G2 cells with dbcAMP increased by 2-fold the phosphorylation of PKC, a hallmark of its activation.…”

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confidence: 84%

cAMP-induced PKCζ activation increases functional CXCR4 expression on human CD34+ hematopoietic progenitors

Goichberg

Kalinkovich

Borodovsky

et al. 2006

Blood

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Chemokines are key regulators of hematopoiesis and host defense. We report here that functional expression of the chemokine receptor CXCR4 on human immature CD34 ؉ hematopoietic progenitors was increased as a result of sustained elevation in cellular cAMP by dbcAMP and prostaglandin E2. This effect of cAMP was specifically mediated by PKC activity. CXCR4 expression and PKC activation by cAMP were decreased after the inhibition of cAMP effector-Rap1 by Spa1 overexpression. Interference with the activation of Rac1, a downstream target of Rap1, prevented the cAMPinduced increase in PKC activity and CXCR4 levels. Functional manifestation of the effects of cAMP-elevating agents revealed an increased ability of human CD34 ؉ cells to transmigrate the bone marrow (BM) endothelial layer and adhere to BM stroma in vitro, and it augmented the homing potential to the BM and spleens of immunodeficient mice in a Rac1-and a PKC-dependent manner. cAMP-and TNF␣-stimulated pathways converged in PKC-activated CXCR4 expression and MMP-2/MMP-9 secretion. cAMP treatment had a beneficial effect on CD34 ؉ cell survival in a PKC-mediated fashion. Taken IntroductionConsiderable effort has been invested in recent years toward understanding the mechanisms that govern hematopoietic stem/ progenitor cell trafficking and development. Chemokine stromal cell-derived factor-1 (SDF-1/CXCL12) is the only known powerful chemoattractant for defined populations of primitive human (CD34 ϩ CD38 Ϫ/low ) and murine (Sca-1 ϩ Thy-1 low c-kit ϩ Lin Ϫ ) hematopoietic progenitor cells. [1][2][3] The primary receptor for SDF-1, CXCR4, is expressed on a variety of immature and mature hematopoietic cells and on neuronal, endothelial, and epithelial cells. [4][5][6] Multiple studies have demonstrated major roles for SDF-1/CXCR4 interaction in human stem cell migration in vivo. Mice lacking either SDF-1 or CXCR4 exhibit several lethal defects, including impairment in hematopoiesis and stem cell seeding of the fetal BM. [7][8][9] We have previously shown that homing and engraftment of human CD34 ϩ CD38 Ϫ/low hematopoietic progenitors transplanted into immunodeficient mice are regulated by cell surface human CXCR4 expression and BMproduced murine SDF-1. 2,[10][11][12][13] The in vitro migratory capacity of enriched CD34 ϩ progenitors, particularly the expression and functionality of CXCR4 on these cells, directly correlates with clinical hematopoietic recovery after autologous stem cell transplantation. [14][15][16] Thus, understanding the mechanisms and molecular pathways that affect CXCR4 expression and cellular signaling might have important implications for clinical stem/ progenitor cell transplantation.Recently, we identified a specific isoform of the PKC family, atypical PKC, as a key regulator of SDF-1/CXCR4-activated signaling in human hematopoietic progenitors, demonstrating that ectopic PKC expression increases SDF-1-induced motility, whereas the inhibition of PKC activity impairs survival, proliferation, adhesion and, engraftment of immature CD34 ϩ proge...

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confidence: 84%

cAMP-induced PKCζ activation increases functional CXCR4 expression on human CD34+ hematopoietic progenitors

Goichberg

Kalinkovich

Borodovsky

et al. 2006

Blood

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“…cAMP stimulates hepatocyte taurocholate (53) and intestinal fructose (8) transport in rats. It turns out that the cAMPstimulated increases in taurocholate transport can be prevented by PI3-kinase and Akt inhibitors and involves the translocation of NTCP transporters to the plasma membrane of hepatocytes (35). Although we did not use PI3-kinase and PKB inhibitors in our cAMP experiments (8), it is interesting to note that the fructose-induced fructose transport in rat neonates that can be inhibited by dideoxyadenosine (an inhibitor of adenylyl cyclase) in previous work has also been shown to be inhibited by PI3-kinase and Akt inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Fructose-induced increases in neonatal rat intestinal fructose transport involve the PI3-kinase/Akt signaling pathway

Cui¹,

Schlesier²,

Fisher³

et al. 2005

American Journal of Physiology-Gastrointestinal and Liver Physi

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Cui, Xue-Lin, Anna M. Schlesier, Elda L. Fisher, Carla Cerqueira, and Ronaldo P. Ferraris. Fructose-induced increases in neonatal rat intestinal fructose transport involve the PI3-kinase/Akt signaling pathway. Am J Physiol Gastrointest Liver Physiol 288: G1310 -G1320, 2005. First published February 3, 2005 doi:10.1152/ajpgi.00550.2004.-Expression of rat glucose transporter-5 (GLUT5) is tightly regulated during development. Expression and activity are low throughout the suckling and weaning stages, but perfusion of the small intestinal lumen with fructose solutions during weaning precociously enhances GLUT5 activity and expression. Little is known, however, about the signal transduction pathways involved in the substrate-induced precocious GLUT5 development. We found that wortmannin and LY-294002, inhibitors of phosphatidylinositol 3-kinase (PI3-kinase) specifically inhibited the increase in fructose uptake rate and brushborder GLUT5 protein abundance but not GLUT5 mRNA abundance. Perfusion of EGF, an activator of PI3-kinase, also resulted in a marked wortmannin-inhibitable increase in fructose uptake. Perfusion of fructose for 4 h increased cytosolic immunostaining of phosphatidylinositol-3,4,5-triphosphate (PIP 3), the primary product of PI3-kinase, mainly in the mid-to upper-villus regions in which the brush-border membrane also stained strongly with GLUT5. Perfusion of glucose for 4 h had little effect on fructose or glucose uptake and PIP 3 or GLUT5 staining. SH-5, an Akt inhibitor, prevented the increase in fructose uptake and GLUT5 protein induced by fructose solutions, and had no effect on glucose uptake. The PI3-kinase/Akt signaling pathway may be involved in the synthesis and/or recruitment to the brush border of GLUT5 transporters by luminal fructose in the small intestine of weaning rats. Increases in fructose transport during the critical weaning period when rats are shifting to a new diet may be modulated by several signaling pathways whose cross talk during development still needs to be elucidated. development; glucose; intestine; epidermal growth factor; mucosa BECAUSE OF DRAMATIC INCREASES in consumption of soft drinks and fruit juices, per capita consumption of fructose in the United States has increased by 10 times in 30 yr to almost 60 g fructose per day (4, 39). Paralleling this remarkable increase in fructose consumption is an alarming increase in incidence of obesity and in prevalence of type II diabetes (4,14). What makes this correlation disturbing is that per capita fructose consumption in very young children has increased faster than that of the general population and in the 1980s was already ϳ30 -40 g fructose per day representing 10% of their energy intake (39). The top 10th percentile of subjects in all age groups typically consume approximately two times more fructose, exposing this particular age group (1-6 yr of age) to potential metabolic derangements caused by excessive fructose consumption. There are very few studies on physiological adaptations to excessive fructose consumpti...

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“…The p38 MAPK activity was determined from the ratio of phosphorylated (Thr 180 /Tyr 182 ) p38 MAPK (active form) to total p38 MAPK (44), and the activity of PKB (PKB) was determined from the ratio of phosphorylated PKB (active form) to total PKB (23,45). The determination of the activities of p38␣ and p38␤ MAPKs in cells transfected with FLAG-tagged p38␣ and p38␤ MAPKs involved immunoprecipitation of FLAG followed by immunoblot analysis of phosphorylated p38 and FLAG.…”

Section: Methodsmentioning

confidence: 99%

Cyclic AMP stimulates Mrp2 translocation by activating p38α MAPK in hepatic cells

Schonhoff¹,

Webster

Anwer³

2010

American Journal of Physiology-Gastrointestinal and Liver Physi

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Schonhoff CM, Webster CRL, Anwer MS. Cyclic AMP stimulates Mrp2 translocation by activating p38␣ MAPK in hepatic cells. Am J Physiol Gastrointest Liver Physiol 298: G667-G674, 2010. First published March 4, 2010 doi:10.1152/ajpgi.00506.2009 induces translocation of multidrug resistant protein 2 (Mrp2) to the canalicular membrane and activates p38 MAPK in rat hepatocytes. In this study, we tested the hypothesis that cAMPinduced Mrp2 translocation may be mediated via p38 MAPK. Studies were conducted in rat hepatocytes and in a human hepatoma cell line, HuH-7. In rat hepatocytes, cAMP increased Mrp2 translocation and p38 MAPK activity. These effects of cAMP were inhibited by SB203580, an inhibitor of p38 MAPK. Wortmannin, a specific inhibitor of phosphoinositide-3-kinase (PI3K), did not inhibit cAMP induced activation of p38 MAPK, indicating PI3K-independent activation of p38 MAPK by cAMP. To further define the role of p38 MAPK, molecular approaches were used to up-or downregulate p38 MAPK activity in HuH-7 cells using constitutively active (CA) and dominant-negative (DN) MAPK kinase 3 and 6 (MKK3/6). MKK3/6 are upstream kinases responsible for the activation of p38 MAPK. Cells transfected with CAMKK6 showed increased p38 MAPK activity and MRP2 translocation compared with empty vector. cAMPinduced activation of p38 MAPK was inhibited in cells transfected with DNMKK3/6 and DNMKK3, but not with DNMKK6. DNMKK3/6 and DNMKK3 also inhibited cAMP-induced MRP2 translocation. cAMP selectively activated p38␣ MAPK in HuH-7 cells. Knockdown of p38␣ MAPK by short heterodimer RNA resulted in decreased level of p38 MAPK and failure of cAMP to stimulate MRP2 translocation. Taken together, these results suggest that cAMPinduced MRP2 translocation in hepatic cells is mediated via PI3K-independent and MKK3-mediated activation of p38␣ MAPK. p38 MAPK isoforms; rat hepatocytes; Huh-7 cells; MAPK kinase; phosphoinositide-3-kinase

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Cross-talk between Protein Kinases Cζ and B in Cyclic AMP-mediated Sodium Taurocholate Co-transporting Polypeptide Translocation in Hepatocytes

Cited by 59 publications

References 50 publications

cAMP-induced PKCζ activation increases functional CXCR4 expression on human CD34+ hematopoietic progenitors

cAMP-induced PKCζ activation increases functional CXCR4 expression on human CD34+ hematopoietic progenitors

Fructose-induced increases in neonatal rat intestinal fructose transport involve the PI3-kinase/Akt signaling pathway

Cyclic AMP stimulates Mrp2 translocation by activating p38α MAPK in hepatic cells

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