Protein kinase A phosphorylation of RhoA mediates the morphological and functional effects of cyclic AMP in cytotoxic lymphocytes.

Lang, Paul; Gesbert, Franck; Delespine-Carmagnat, Maryvonnick; Stancou, Rodica; Pouchelet, M.; Bertoglio, Jacques

doi:10.1002/j.1460-2075.1996.tb00383.x

Cited by 520 publications

(470 citation statements)

References 60 publications

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“…In fact, our results are not surprising considering the following points. Ser phosphorylation of RhoA is normally related to its inhibition by a guaninenucleotide dissociation inhibitor (GDI; Lang et al 1996;Ellerbroek et al 2003). In this case, GTP-bound RhoA is not amenable to pull-down analysis (Ellerbroek et al 2003), which is inconsistent with our previous pull-down data (Rosso et al 2002a).…”

Section: Discussionmentioning

confidence: 62%

“…Relevant to adenosine-induced pituicyte stellation, protein kinase A phosphorylation of a Ser residue has been suggested as one mechanism for RhoA inhibition (Lang et al 1996;Ellerbroek et al 2003). This indeed might represent an intriguing link between metabotropic receptor stimulation and monomeric GTPase inhibition.…”

Section: Discussionmentioning

confidence: 99%

“…4, lower right panel), consistent with our previous finding that adenosine induces stellation via RhoA inhibition. In order to determine whether the mechanism of inhibition involves serine phosphorylation of RhoA, as was shown in other cell types (Lang et al 1996;Ellerbroek et al 2003), we transfected pituicytes with two types of mutants: RhoA-S188A, a phosphorylation-resistant mutant, or RhoA-S188D, a phosphomimetic mutant. The former had no effect on spread pituicytes nor did it prevent adenosine from inducing stellation, whereas the latter mutant by itself did not induce stellation (Fig.…”

Section: Effects Of Monomeric Gtpase Expression On Pituicyte Morphologymentioning

confidence: 99%

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Pituicyte Stellation is Prevented by RhoA-or Cdc42-Dependent Actin Polymerization

et al. 2007

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Our aim was to shed light on different steps leading from metabotropic receptor activation to changes in cell shape, such as those that characterize the morphological plasticity of neurohypophysial astrocytes (pituicytes). Using explant cultures of adult rat pituicytes, we have previously established that adenosine A1 receptor activation induces stellation via inhibition of RhoA monomeric GTPase and subsequent disruption of actin stress fibers. Here, we rule out RhoA phosphorylation as a mechanism for that inhibition. Rather, our results are more consistent with involvement of a GTPase-activating protein (GAP). siRNA and pull-down experiments suggest that a step downstream of RhoA might involve Cdc42, another GTPase of the Rho family. However, RhoA activation, e.g., in the presence of serum, induces stress fibers, whereas direct Cdc42 activation appears to confine actin within a submembrane-i.e., cortical-network, which also prevents stellation. Therefore, we propose that RhoA may activate Cdc42 in parallel with an effector, such as p160Rho-kinase, that induces and maintains actin stress fibers in a dominant fashion. Racl is not involved in the stellation process per se but appears to induce a dendritogenic effect. Ultimately, it may be stated that pituicyte stellation is inducible upon mere actin depolymerization, and preventable upon actin organization, be it in the form of stress fibers or in a cortical configuration.

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Section: Discussionmentioning

confidence: 62%

Section: Discussionmentioning

confidence: 99%

Section: Effects Of Monomeric Gtpase Expression On Pituicyte Morphologymentioning

confidence: 99%

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Pituicyte Stellation is Prevented by RhoA-or Cdc42-Dependent Actin Polymerization

et al. 2007

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“…One potential mechanism of PKA-dependent barrier protection is PKA-mediated phosphorylation of Rho-GDP dissociation inhibitor, a negative regulator of small GTPase Rho, which results in Rho inactivation and blocks Rho-dependent mechanism of EC hyperpermeability [21]. Activation of cAMP/PKA-mediated signaling also has an inhibitory effect on RhoA activity [23] by direct phosphorylation of RhoA [23,24]. In contrast to RhoA, Rac and Cdc42 can be activated by PKA without direct phosphorylation [25,26], but via activation of guanine nucleotide exchange factors (GEFs)Tiam1 and Trio, which have consensus PKA phosphorylation sites [27].…”

Section: Introductionmentioning

confidence: 99%

Prostaglandins PGE2 and PGI2 promote endothelial barrier enhancement via PKA- and Epac1/Rap1-dependent Rac activation

Birukova

Zagranichnaya

et al. 2007

Experimental Cell Research

264

267

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Prostaglandin E 2 (PGE 2 ) and prostacyclin are lipid mediators produced by cyclooxygenase and implicated in the regulation of vascular function, wound repair, inflammatory processes, and acute lung injury. Although protective effects of these prostaglandins (PGs) are associated with stimulation of intracellular cAMP production, the crosstalk between cAMP-activated signal pathways in the regulation of endothelial cell (EC) permeability is not well understood. We studied involvement of cAMP-dependent kinase (PKA), cAMP-Epac-Rap1 pathway, and small GTPase Rac in the PGsinduced EC barrier protective effects and cytoskeletal remodeling. PGE 2 and PGI 2 synthetic analog beraprost increased transendothelial electrical resistance and decreased dextran permeability, enhanced peripheral F-actin rim and increased intercellular adherens junction areas reflecting EC barrier-protective response. Furthermore, beraprost dramatically attenuated thrombin-induced Rho activation, MLC phosphorylation and EC barrier dysfunction. In vivo, beraprost attenuated lung barrier dysfunction induced by high tidal volume mechanical ventilation. Both PGs caused cAMPmediated activation of PKA-, Epac/Rap1-and Tiam1/Vav2-dependent pathways of Rac1 activation and EC barrier regulation. Knockdown of Epac, Rap1, Rac-specific exchange factors Tiam1 and Vav2 using siRNA approach, or inhibition of PKA activity decreased Rac1 activation and PGinduced EC barrier enhancement. Thus, our results show that barrier-protective effects of PGE 2 and prostacyclin on pulmonary EC are mediated by PKA and Epac/Rap pathways, which converge on Rac activation and lead to enhancement of peripheral actin cytoskeleton and adherens junctions. These mechanisms may mediate protective effects of PGs against agonist-induced lung vascular barrier dysfunction in vitro and against mechanical stress-induced lung injury in vivo.

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“…Therefore, the cytoskeletal rearrangements downstream of cAMP production are consistent with an inhibition of RhoA and a stimulation of Rac1 and Cdc42. In accordance with these expected changes, PKA, activated upon increases in cAMP, directly phosphorylates RhoA to inhibit its function [19,20] and indirectly activates Cdc42 [21], possibly through phosphorylation of guanine nucleotide exchange factor for Cdc42 [22]. Importantly, although both the secramines and pirl1 inhibit Cdc42 activation, neither inhibits activation of RhoA as monitored by stress fiber stability [5,9].…”

Section: Discussionmentioning

confidence: 81%

The Cdc42 inhibitor secramine B prevents cAMP-induced K+ conductance in intestinal epithelial cells

Pelish

Ciesla

Tanaka

et al. 2006

Biochemical Pharmacology

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Cyclic AMP-(cAMP) and calcium-dependent agonists stimulate chloride secretion through the coordinated activation of distinct apical and basolateral membrane channels and ion transporters in mucosal epithelial cells. Defects in the regulation of Cl -transport across mucosal surfaces occur with cystic fibrosis and V. cholerae infection and can be life threatening. Here we report that secramine B, a small molecule that inhibits activation of the Rho GTPase Cdc42, reduced cAMPstimulated chloride secretion in the human intestinal cell line T84. Secramine B interfered with a cAMP-gated and Ba 2+ -sensitive K + channel, presumably KCNQ1/KCNE3. This channel is required to maintain the membrane potential that sustains chloride secretion. In contrast, secramine B did not affect the Ca 2+ -mediated chloride secretion pathway, which requires a separate K + channel activity from that of cAMP. Pirl1, another small molecule structurally unrelated to secramine B that also inhibits Cdc42 activation in vitro, similarly inhibited cAMPdependent but not Ca 2+ -dependent chloride secretion. These results suggest that Rho GTPases may be involved in the regulation of the chloride secretory response and identify secramine B an inhibitor of cAMP-dependent K + conductance in intestinal epithelial cells.

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Protein kinase A phosphorylation of RhoA mediates the morphological and functional effects of cyclic AMP in cytotoxic lymphocytes.

Cited by 520 publications

References 60 publications

Pituicyte Stellation is Prevented by RhoA-or Cdc42-Dependent Actin Polymerization

Pituicyte Stellation is Prevented by RhoA-or Cdc42-Dependent Actin Polymerization

Prostaglandins PGE2 and PGI2 promote endothelial barrier enhancement via PKA- and Epac1/Rap1-dependent Rac activation

The Cdc42 inhibitor secramine B prevents cAMP-induced K+ conductance in intestinal epithelial cells

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