Cdc42 and Rac Stimulate Exocytosis of Secretory Granules by Activating the Ip3/Calcium Pathway in Rbl-2h3 Mast Cells

Hong-Geller, Elizabeth; Cerione, Richard A.

doi:10.1083/jcb.148.3.481

Cited by 137 publications

(136 citation statements)

References 51 publications

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“…Small GTPases Rac1, Rac2, and Cdc42 have been implicated in granule exocytosis in mast cells and neutrophils through modulation of the actin cytoskeleton (43,44) and have been associated with cytokine secretion in other cells, such as IL-8 from polarized epithelial cells (45). However, no specific role for Rho GTPases in cytokine secretion from SMC has yet been established.…”

Section: Discussionmentioning

confidence: 99%

P2Y2 Receptor-mediated Lymphotoxin-α Secretion Regulates Intercellular Cell Adhesion Molecule-1 Expression in Vascular Smooth Muscle Cells

Seye

Ağca

Derbigny

2012

Journal of Biological Chemistry

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Background: Lymphotoxin-␣ (LTA) is involved in the pathogenesis of atherosclerosis. Results: The P2Y 2 nucleotide receptor (P2Y 2 R) recruits filamin A to activate Rho signaling upstream of LTA secretion leading to intercellular cell adhesion molecule-1 expression. Conclusion: P2Y 2 R regulates LTA gene activation and secretion in vascular smooth muscle cells. Significance: This suggests that P2Y 2 R is an important regulator of vascular inflammation.

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Section: Discussionmentioning

confidence: 99%

P2Y2 Receptor-mediated Lymphotoxin-α Secretion Regulates Intercellular Cell Adhesion Molecule-1 Expression in Vascular Smooth Muscle Cells

Seye

Ağca

Derbigny

2012

Journal of Biological Chemistry

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“…In mast and chromaffin cells, one or more members of the Rho family play an active role in the exocytotic process (27,28,59,60). In addition, Cdc42 and Rac control regulated secretion in pancreatic ␤-cells (61).…”

Section: Discussionmentioning

confidence: 99%

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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“…Introduction of Rac into permeabilized mast cells causes exocytic secretion [19], and expression of dominant-negative forms of Rac and Cdc42 inhibits antigen-mediated degranulation [20]. This inhibition is rescued by the addition of calcium ionophores, implying that Rac and Cdc42 are upstream of the calcium influx pathway [21,22]. Patch clamp studies in the same system showed that Rac/ Cdc42 are involved in calcium mobilization, in part through the regulation of calcium release-activated calcium channels [23].…”

Section: Introductionmentioning

confidence: 99%

“…Previous studies have shown that the activation of Rho GTPases is PI3K-independent in RBL-2H3 cells [24]. PLCc was found to directly bind Cdc42 in vitro in these cells [21], suggesting that PLCc could be a downstream effector of Rho GTPases in response to antigen stimulation. In contrast, we have here examined the role of PLCc in the upstream regulation of Rac and Cdc42.…”

Section: Introductionmentioning

confidence: 99%

Phospholipase Cγ negatively regulates Rac/Cdc42 activation in antigen‐stimulated mast cells

El‐Sibai

Backer

2006

Eur J Immunol

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The Rho GTPases Rac and Cdc42 play a central role in the regulation of secretory and cytoskeletal responses in antigen-stimulated mast cells. In this study, we examine the kinetics and mechanism of Rac and Cdc42 activation in the rat basophilic leukemia RBL-2H3 cells. The activation kinetics of both Rac and Cdc42 show a biphasic profile, consisting of an early transient peak at 1 min and a late sustained activation phase at 20-40 min. The inhibition of phospholipase C (PLC)c causes a twofold increase in Rac and Cdc42 activation that coincides with a dramatic production of atypical filopodialike structures. Inhibition of protein kinase C using bisindolylmaleimide mimics the effect of PLCc inhibition on Rac activation, but not on Cdc42 activation. In contrast, depletion of intracellular calcium leads to a complete inhibition of the early activation peak of both Rac and Cdc42, without significant effects on the late sustained activation. These data suggest that PLCc is involved in a negative feedback loop that leads to the inhibition of Rac and Cdc42. They also suggest that the presence of intracellular calcium is a prerequisite for both Rac and Cdc42 activation. IntroductionMast cells participate in the pathogenesis of immediate hypersensitivity and allergic reactions in humans [1]. Moreover, mast cells are important contributors to airway hyper-responsiveness that occurs in asthmatic inflammation [2]. In response to allergens and other exogenous stimuli, mast cells accumulate in the airway smooth muscle and in the bronchial intraepithelial layer [3]. The activation of mast cells, through the crosslinking of the FceRI, leads to the release of pre-formed early-phase inflammatory mediators and vasoactive substances from granules. It also leads to the in situ production of cytokines and bioactive lipids that contribute to the late-phase manifestation of the asthmatic reaction [4].Aggregation of FceRI on the surface of mast cells in response to multivalent ligand binding initiates a cascade of downstream signaling effectors that leads to degranulation [5]. These include phosphatidylinositol 3-kinase (PI3K), the guanine nucleotide exchange factor Vav, and phospholipase C (PLC)c1 [6]. The early activation of PLCc1 results in the generation of inositol 1,4,5-triphosphate (IP 3 ) and diacylglycerol. These two second messengers lead to increases in cytoplasmic calcium and activation of calcium/diacylglycerol-regulated isoforms of protein kinase C (PKC) which culminate in granule margination and exocytosis [7]. PI3K plays an important regulatory role as an upstream activator of PLCc1, as well as a regulator of calcium flux during mast cell degranulation [8][9][10][11][12][13].Members of the Rho family of small GTPases also regulate signaling events in mast cells [14][15][16]. In the rat basophilic leukemia (RBL-2H3) cells, Rac and Cdc42 have been implicated in the control of the FceRImediated phagocytosis and the regulation of migration, In conjunction with the secretory response, antigenstimulated mast cells undergo drama...

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Cdc42 and Rac Stimulate Exocytosis of Secretory Granules by Activating the Ip3/Calcium Pathway in Rbl-2h3 Mast Cells

Cited by 137 publications

References 51 publications

P2Y2 Receptor-mediated Lymphotoxin-α Secretion Regulates Intercellular Cell Adhesion Molecule-1 Expression in Vascular Smooth Muscle Cells

P2Y2 Receptor-mediated Lymphotoxin-α Secretion Regulates Intercellular Cell Adhesion Molecule-1 Expression in Vascular Smooth Muscle Cells

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

Phospholipase Cγ negatively regulates Rac/Cdc42 activation in antigen‐stimulated mast cells

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