scholarly journals Rho1 regulates apoptosis via activation of the JNK signaling pathway at the plasma membrane

2010 ◽  
Vol 189 (2) ◽  
pp. 311-323 ◽  
Author(s):  
Amanda L. Neisch ◽  
Olga Speck ◽  
Beth Stronach ◽  
Richard G. Fehon
Keyword(s):  
Plasma Membrane ◽  
Cell Survival ◽  
Cell Shape ◽  
Rho Kinase ◽  
Small Gtpase ◽  
Cell Cortex ◽  
Jnk Pathway ◽  
Jnk Signaling ◽  
Upstream Regulator ◽  
Jnk Signaling Pathway

Precisely controlled growth and morphogenesis of developing epithelial tissues require coordination of multiple factors, including proliferation, adhesion, cell shape, and apoptosis. RhoA, a small GTPase, is known to control epithelial morphogenesis and integrity through its ability to regulate the cytoskeleton. In this study, we examine a less well-characterized RhoA function in cell survival. We demonstrate that the Drosophila melanogaster RhoA, Rho1, promotes apoptosis independently of Rho kinase through its effects on c-Jun NH2-terminal kinase (JNK) signaling. In addition, Rho1 forms a complex with Slipper (Slpr), an upstream activator of the JNK pathway. Loss of Moesin (Moe), an upstream regulator of Rho1 activity, results in increased levels of Rho1 at the plasma membrane and cortical accumulation of Slpr. Together, these results suggest that Rho1 functions at the cell cortex to regulate JNK activity and implicate Rho1 and Moe in epithelial cell survival.

scholarly journals hCG Improves Luteal Function and Promotes Progesterone Output through the Activation of JNK Pathway in the Luteal Granulosa Cells of the Stimulated IVF Cycles†

2020 ◽  
Vol 102 (6) ◽  
pp. 1270-1280 ◽  
Author(s):  
Gamze Bildik ◽  
Nazli Akin ◽  
Yashar Esmaeilian ◽  
Francesko Hela ◽  
Kayhan Yakin ◽  
...  
Keyword(s):  
Luteinizing Hormone ◽  
Signaling Pathway ◽  
Granulosa Cells ◽  
Luteal Phase ◽  
Steroidogenic Enzymes ◽  
Jnk Pathway ◽  
Jnk Signaling ◽  
Luteal Function ◽  
Jnk Signaling Pathway

Abstract Human chorionic gonadotropin (hCG) is a luteotropic hormone that promotes the survival and steroidogenic activity of corpus luteum (CL) by acting through luteinizing hormone receptors (LHRs) expressed on luteinized theca and granulosa cells (GCs). Therefore, it is used to support luteal phase in in vitro fertilization (IVF) cycles to improve clinical pregnancy rates and prevent miscarriage. However, the molecular mechanism underlying this action of hCG is not well characterized. To address this question, we designed an in vitro translational research study on the luteal GCs obtained from 58 IVF patients. hCG treatment at different concentrations and time points activated c-Jun N-terminal kinase (JNK) pathway and significantly increased its endogenous kinase activity along with upregulated expression of steroidogenic enzymes (steroidogenic acute regulatory protein (stAR), 3β-Hydroxysteroid dehydrogenase (3β-HSD)) in a dose-dependent manner in the luteal GCs. As a result, in vitro P production of the cells was significantly enhanced after hCG. When JNK pathway was inhibited pharmacologically or knocked-down with small interfering RNA luteal function was compromised, P4 production was declined along with the expression of stAR and 3β-HSD in the cells. Further, hCG treatment after JNK inhibition failed to correct the luteal defect and promote P4 output. Similar to hCG, luteinizing hormone (LH) treatment improved luteal function as well and this action of LH was associated with JNK activation in the luteal GCs. These findings could be important from the perspective of CL biology and luteal phase in human because we for the first time identify a critical role for JNK signaling pathway downstream LHR activation by hCG/LH in luteal GCs. Summary Sentence JNK signaling pathway plays a central role in the upregulated expression of the steroidogenic enzymes StAR and 3b-HSD and augmented progesterone production by hCG/LH in human luteal granulosa cells.

Recycling domains in plant cell morphogenesis: small GTPase effectors, plasma membrane signalling and the exocyst

2010 ◽  
Vol 38 (2) ◽  
pp. 723-728 ◽  
Author(s):  
Viktor Žárský ◽  
Martin Potocký
Keyword(s):  
Plasma Membrane ◽  
Plant Cell ◽  
Secretory Pathway ◽  
Root Hairs ◽  
Small Gtpases ◽  
Small Gtpase ◽  
Cell Cortex ◽  
Membrane Phospholipids ◽  
Recycling Endosome ◽  
Regulatory Module

The Rho/Rop small GTPase regulatory module is central for initiating exocytotically ACDs (active cortical domains) in plant cell cortex, and a growing array of Rop regulators and effectors are being discovered in plants. Structural membrane phospholipids are important constituents of cells as well as signals, and phospholipid-modifying enzymes are well known effectors of small GTPases. We have shown that PLDs (phospholipases D) and their product, PA (phosphatidic acid), belong to the regulators of the secretory pathway in plants. We have also shown that specific NOXs (NADPH oxidases) producing ROS (reactive oxygen species) are involved in cell growth as exemplified by pollen tubes and root hairs. Most plant cells exhibit several distinct plasma membrane domains (ACDs), established and maintained by endocytosis/exocytosis-driven membrane protein recycling. We proposed recently the concept of a ‘recycling domain’ (RD), uniting the ACD and the connected endosomal recycling compartment (endosome), as a dynamic spatiotemporal entity. We have described a putative GTPase–effector complex exocyst involved in exocytic vesicle tethering in plants. Owing to the multiplicity of its Exo70 subunits, this complex, along with many RabA GTPases (putative recycling endosome organizers), may belong to core regulators of RD organization in plants.

Effect of pharmacologic inhibition of c-Jun N-terminal kinase (JNK) signaling pathway on cell proliferation and cell cycle progression in human granulosa cell tumor.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e22004-e22004
Author(s):  
Ozgur Oktem ◽  
Meltem Muftuoglu ◽  
Filiz Senbabaoglu ◽  
Bulent Urman
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Signaling Pathway ◽  
Granulosa Cell ◽  
Dependent Manner ◽  
Jnk Pathway ◽  
Jnk Signaling ◽  
Curative Therapy ◽  
Jnk Signaling Pathway ◽  
Dose Dependent

e22004 Background: No data are available regarding the signaling pathways that controls the proliferation of granulosa cell tumors (GCT). Preliminary findings showing the activation of c-Jun N-terminal kinase (JNK) signaling pathway in the proliferating granulosa cells has led us to investigate the role of this pathway in human GCT. Methods: Human GCT line COV 434 was used. Cell proliferation was monitored real-time quantitatively for 120h using an impedance-based system. Two different pharmacologic JNK inhibitors SP600125 and AS601245 were used. Their inhibitory concentrations were determined in western blot. Cell cycle was analyzed with flow cytometry and apoptosis with yo-pro-1 staining. Results: First, the growth characteristics of this cell line was delineated (Table 1A). Then the cells were treated with the inhibitors at the indicated doses during the log phase. Their proliferation was significantly halted in a dose-dependent manner by both inhibitors (Table 1B). Furthermore, the cells failed to complete mitosis, and began to accumulate at G2 in a dose dependent manner when JNK pathway was interrupted with AS601245 (59%) and SP600125 (39%) during G2/M transition compared to control cells (7%) proceeding through G2/M phase regularly (p<0.001). Compared to 3.5% of control cells, 14% and 30% of the cells underwent apoptosis when treated with 50 µM SP600125 and AS601245, respectively. At 100 µM, the apoptotic fraction increased to 68% and 76%, respectively (p<0.01). Conclusions: These results suggest that pharmacologic manipulation of JNK pathway may provide a therapeutic benefit in the treatment of GCT for which currently, no curative therapy exists beyond surgery. Funded by a Grant to Ozgur Oktem (TUBITAK109S164). [Table: see text]

scholarly journals Association of the Myosin-binding Subunit of Myosin Phosphatase and Moesin: Dual Regulation of Moesin Phosphorylation by Rho-associated Kinase and Myosin Phosphatase

1998 ◽  
Vol 141 (2) ◽  
pp. 409-418 ◽  
Author(s):  
Yuko Fukata ◽  
Kazushi Kimura ◽  
Noriko Oshiro ◽  
Hideyuki Saya ◽  
Yoshiharu Matsuura ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Phosphatase Activity ◽  
Mdck Cells ◽  
Rho Kinase ◽  
Small Gtpase ◽  
Myosin Phosphatase ◽  
Membrane Ruffling ◽  
Amino Terminal ◽  
Myosin Binding ◽  
Binding Subunit

The small GTPase Rho is believed to regulate the actin cytoskeleton and cell adhesion through its specific targets. We previously identified the Rho targets: protein kinase N, Rho-associated kinase (Rho- kinase), and the myosin-binding subunit (MBS) of myosin phosphatase. We found that in MDCK epithelial cells, MBS accumulated at the tetradecanoylphorbol-13-acetate (TPA)-induced membrane ruffling area, where moesin, a member of the ERM (ezrin, radixin, and moesin) family, was localized. Neither membrane ruffling nor an accumulation of moesin and MBS at the free-end plasma membrane was induced when MDCK cells were stimulated with TPA after the microinjection of C3, which ADP-ribosylates and inactivates Rho. MBS was colocalized with moesin at the cell–cell contact sites in MDCK cells. We also found that moesin was coimmunoprecipitated with MBS from MDCK cells. Recombinant MBS interacted with the amino-terminal domains of moesin and ezrin. Myosin phosphatase composed of the catalytic subunit and MBS showed phosphatase activity toward moesin, which was phosphorylated by Rho-kinase. The phosphatase activity was inhibited when MBS was phosphorylated by Rho-kinase. These results suggest that MBS is recruited with moesin to the plasma membrane and that myosin phosphatase and Rho-kinase regulate the phosphorylation state of moesin downstream of Rho.

scholarly journals Exophilin8 transiently clusters insulin granules at the actin-rich cell cortex prior to exocytosis

2011 ◽  
Vol 22 (10) ◽  
pp. 1716-1726 ◽  
Author(s):  
Kouichi Mizuno ◽  
José S. Ramalho ◽  
Tetsuro Izumi
Keyword(s):  
Plasma Membrane ◽  
Secretory Granules ◽  
Small Gtpase ◽  
Cell Cortex ◽  
Cortical Actin ◽  
Insulin Granules ◽  
Myosin Va ◽  
Exogenous Expression ◽  
Mutation Analyses

Exophilin8/MyRIP/Slac2-c is an effector protein of the small GTPase Rab27a and is specifically localized on retinal melanosomes and secretory granules. We investigated the role of exophilin8 in insulin granule trafficking. Exogenous expression of exophilin8 in pancreatic β cells or their cell line, MIN6, polarized (exophilin8-positive) insulin granules at the cell corners, where both cortical actin and the microtubule plus-end–binding protein, EB1, were present. Mutation analyses indicated that the ability of exophilin8 to act as a linker between Rab27a and myosin Va is essential for its granule-clustering activity. Moreover, exophilin8 and exophilin8-associated insulin granules were markedly stable and immobile. Total internal reflection fluorescence microscopy indicated that exophilin8 restricts the motion of insulin granules at a region deeper than that where another Rab27a effector, granuphilin, accumulates docked granules directly attached to the plasma membrane. However, the exophilin8-induced immobility of insulin granules was eliminated upon secretagogue stimulation and did not inhibit evoked exocytosis. Furthermore, exophilin8 depletion prevents insulin granules from being transported close to the plasma membrane and inhibits their fusion. These findings indicate that exophilin8 transiently traps insulin granules into the cortical actin network close to the microtubule plus-ends and supplies them for release during the stimulation.

scholarly journals Terminal differentiation of human granulosa cells as luteinization is reversed by activin-A through silencing of Jnk pathway

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Gamze Bildik ◽  
Nazli Akin ◽  
Yashar Esmaeilian ◽  
Francesko Hela ◽  
Ceren Sultan Yildiz ◽  
...  
Keyword(s):  
Corpus Luteum ◽  
Signaling Pathway ◽  
Granulosa Cells ◽  
Molecular Mechanisms ◽  
Terminal Differentiation ◽  
Reproductive Technologies ◽  
Activin A ◽  
Jnk Pathway ◽  
Jnk Signaling ◽  
Jnk Signaling Pathway

Abstract Molecular mechanisms underlying luteinization (terminal differentiation of granulosa and theca cells after ovulation) and luteolysis (demise of corpus luteum) are poorly understood in human ovary. Here we report that activin-A, after binding to its cognate receptors induces a functional luteolytic state and reverses luteinization phenotype by downregulating the expression of the steroidogenic enzymes, LH receptor and VEGF and reducing estradiol (E2) progesterone (P4) production and upregulating FSH receptor and cyclin D1 expression in human primary luteinized granulosa cells. Further, this action of activin-A involves downregulation of JNK signaling pathway and is opposite to that of human chorionic gonadotropin (hCG), which acts as a luteotropic hormone and improves luteal function through the activation of JNK pathway in the same cell type. Reversal of luteinization phenotype in luteal granulosa cells by activin-A potentially makes this hormone an attractive candidate for use under certain clinical situations, where induction of luteolysis and rapid reduction of endogenous sex steroid levels are beneficial such as ovarian hyperstimulation syndrome (OHSS), in which the ovaries hyper-respond to gonadotropin stimulation by producing too many growing follicles along with development of ascites, pleural effusion, and hemo-concentrations as a result of increased vascular permeability and leakage of intravascular volume into third spaces. Our work unveils a previously undefined role for activin-A and JNK signaling pathway in human corpus luteum biology, that might have a direct clinical impact in assisted reproductive technologies.

scholarly journals LPS Cooperates with Poly-L-Arginine to Promote IL-6 and IL-8 Release via the JNK Signaling Pathway in NCI-H292 Cells

2016 ◽  
Vol 2016 ◽  
pp. 1-7 ◽  
Author(s):  
Ling-Ling Zhang ◽  
Bing Chen ◽  
Xiao-Yun Fan ◽  
Sha-Sha Wu ◽  
Sheng-Quan Zhang ◽  
...  
Keyword(s):  
Synergistic Effect ◽  
Signaling Pathway ◽  
Enzyme Linked Immunosorbent Assay ◽  
Jnk Pathway ◽  
Jnk Signaling ◽  
Time Points ◽  
Phosphorylation Level ◽  
Combined Use ◽  
Jnk Signaling Pathway ◽  
Lps Treatment

Objective. Herein, we aimed to study the mechanism whereby poly-L-arginine (PLA) and lipopolysaccharide (LPS) can synergistically induce the release of interleukin-6 (IL-6) and IL-8 in NCI-H292 cells.Methods. NCI-H292 cells were divided into control, PLA, LPS, and PLA+LPS groups. At various time points, the phosphorylation of JNK in each group was measured by western blotting. Additionally, the productions of IL-6 and IL-8 were assessed using an enzyme-linked immunosorbent assay (ELISA). The effects of SP600125, an inhibitor of the JNK pathway, on the increase of p-JNK, IL-6, and IL-8 were also studied.Results. Our results showed that either PLA or LPS treatment alone can significantly increase the phosphorylation level of JNK in NCI-H292 cells. Of interest was the combined use of PLA and LPS that has a synergistic effect on the phosphorylation of JNK, as well as synergistically inducing the release of IL-6 and IL-8 in NCI-H292 cells. Furthermore, SP600125 significantly inhibited the activation of JNK signal, as well as reducing the productions of IL-6 and IL-8 in response to PLA+LPS stimulation.Conclusions. The JNK signaling pathway contributes to the release of IL-6 and IL-8, which is stimulated by the synergistic actions of PLA+LPS in NCI-H292 cells.

scholarly journals JNK signaling prevents biliary cyst formation through a CASPASE-8–dependent function of RIPK1 during aging

2021 ◽  
Vol 118 (12) ◽  
pp. e2007194118
Author(s):  
Katrin Müller ◽  
Hanna Honcharova-Biletska ◽  
Christiane Koppe ◽  
Michèle Egger ◽  
Lap Kwan Chan ◽  
...  
Keyword(s):  
Cell Death ◽  
Cyst Formation ◽  
Jnk Pathway ◽  
Interacting Protein ◽  
Jnk Signaling ◽  
Age Related ◽  
Polycystic Liver ◽  
Jnk Signaling Pathway ◽  
Stress Signals ◽  
Parenchymal Cells

The c-Jun N-terminal kinase (JNK) signaling pathway mediates adaptation to stress signals and has been associated with cell death, cell proliferation, and malignant transformation in the liver. However, up to now, its function was experimentally studied mainly in young mice. By generating mice with combined conditional ablation of Jnk1 and Jnk2 in liver parenchymal cells (LPCs) (JNK1/2LPC-KO mice; KO, knockout), we unraveled a function of the JNK pathway in the regulation of liver homeostasis during aging. Aging JNK1/2LPC-KO mice spontaneously developed large biliary cysts that originated from the biliary cell compartment. Mechanistically, we could show that cyst formation in livers of JNK1/2LPC-KO mice was dependent on receptor-interacting protein kinase 1 (RIPK1), a known regulator of cell survival, apoptosis, and necroptosis. In line with this, we showed that RIPK1 was overexpressed in the human cyst epithelium of a subset of patients with polycystic liver disease. Collectively, these data reveal a functional interaction between JNK signaling and RIPK1 in age-related progressive cyst development. Thus, they provide a functional linkage between stress adaptation and programmed cell death (PCD) in the maintenance of liver homeostasis during aging.

scholarly journals Suppression of ischemia in arterial occlusive disease by JNK-promoted native collateral artery development

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Kasmir Ramo ◽  
Koichi Sugamura ◽  
Siobhan Craige ◽  
John F Keaney ◽  
Roger J Davis
Keyword(s):  
Blood Flow ◽  
Signaling Pathway ◽  
Arterial Occlusion ◽  
Arterial Occlusive Disease ◽  
Occlusive Disease ◽  
Artery Ligation ◽  
Jnk Pathway ◽  
Jnk Signaling ◽  
Collateral Arteries ◽  
Jnk Signaling Pathway

Arterial occlusive diseases are major causes of morbidity and mortality. Blood flow to the affected tissue must be restored quickly if viability and function are to be preserved. We report that disruption of the mixed-lineage protein kinase (MLK) - cJun NH2-terminal kinase (JNK) signaling pathway in endothelial cells causes severe blockade of blood flow and failure to recover in the murine femoral artery ligation model of hindlimb ischemia. We show that the MLK-JNK pathway is required for the formation of native collateral arteries that can restore circulation following arterial occlusion. Disruption of the MLK-JNK pathway causes decreased Dll4/Notch signaling, excessive sprouting angiogenesis, and defects in developmental vascular morphogenesis. Our analysis demonstrates that the MLK-JNK signaling pathway is a key regulatory mechanism that protects against ischemia in arterial occlusive disease.

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