Protein Kinase A Regulates Rac and Is Required for the Growth Factor-stimulated Migration of Carcinoma Cells

O’Connor, Kathleen L.; Mercurio, Arthur M.

doi:10.1074/jbc.m107235200

Cited by 128 publications

(123 citation statements)

References 39 publications

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“…The Rho GTPases are small GTPases that regulate the actin cytoskeleton (Hall and Nobes, 2000) and have been previously shown to play important roles in axon guidance and other forms of cellular motility (Dickson, 2001;Ng et al, 2002). Recent studies suggest that PKA can regulate the activity of Rho GTPases (Lang et al, 1996;Laudanna et al, 1997;O'Connor and Mercurio, 2001). Other candidate PKA targets likely to be regulated during axon guidance include members of the Enabled (Ena)/ Vasodilator-stimulated phosphoprotein (VASP) family, which have been implicated in the regulation of actin-based motility.…”

Section: Discussionmentioning

confidence: 99%

Direct cAMP Signaling through G-Protein-Coupled Receptors Mediates Growth Cone Attraction Induced by Pituitary Adenylate Cyclase-Activating Polypeptide

et al. 2003

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Developing axons are guided to their appropriate targets by environmental cues through the activation of specific receptors and intracellular signaling pathways. Here we report that gradients of pituitary adenylate cyclase-activating polypeptide (PACAP), a neuropeptide widely expressed in the developing nervous system, induce marked attraction of Xenopus growth cones in vitro. PACAP exerted its chemoattractive effects through PAC1, a PACAP-selective G-protein-coupled receptor (GPRC) expressed at the growth cone. Furthermore, the attraction depended on localized cAMP signaling because it was completely blocked either by global elevation of intracellular cAMP levels using forskolin or by inhibition of protein kinase A using specific inhibitors. Moreover, local direct elevation of intracellular cAMP by focal photolysis of caged cAMP compounds was sufficient to induce growth cone attraction. On the other hand, blockade of Ca 2ϩ , phospholipase C, or phosphatidyl inositol-3 kinase signaling pathways did not affect PACAP-induced growth cone attraction. Finally, PACAP-induced attraction also involved the Rho family of small GTPases and required local protein synthesis. Taken together, our results establish cAMP signaling as an independent pathway capable of mediating growth cone attraction induced by a physiologically relevant peptide acting through GPCRs. Such a direct cAMP pathway could potentially operate in other guidance systems for the accurate wiring of the nervous system.

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Section: Discussionmentioning

confidence: 99%

Direct cAMP Signaling through G-Protein-Coupled Receptors Mediates Growth Cone Attraction Induced by Pituitary Adenylate Cyclase-Activating Polypeptide

et al. 2003

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“…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]. Another GEF Vav2 demonstrates strong GEF exchange activity toward Rac1 and Cdc42 [28].…”

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

262

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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“…Our findings indicate that, in endothelial cells, an elevation of cAMP accelerates ␣ V ␤ 3 -mediated adhesion and promotes Racdependent spreading via activation of PKA. Recently, cAMPdependent PKA activation was reported to induce ␤ 1 -integrin mediated MDA-435 breast carcinoma cell migration in response to growth factors through the activation of Rac and the inhibition of RhoA (34). There is also emerging evidence that PKA can positively and negatively regulate integrin-mediated cell adhesion and migration of carcinoma and sarcoma-derived cell lines, endothelial cells, and neutrophils (33, 34, 44 -46).…”

Section: Pgementioning

confidence: 99%

“…The regulation of cAMP levels may occur through modulation of cAMP generation by AC or degradation by phosphodiesterase. Indeed, growth factor-stimulated carcinoma cell migration was shown to require both cAMP-dependent PKA activity and phosphodiesterase-mediated cAMP degradation (12,34).…”

Section: Pgementioning

confidence: 99%

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Prostaglandin E2 Promotes Integrin αVβ3-dependent Endothelial Cell Adhesion, Rac-activation, and Spreading through cAMP/PKA-dependent Signaling

Dormond¹,

Bezzi

Mariotti

et al. 2002

Journal of Biological Chemistry

142

108

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We have recently reported that the inhibition of endothelial cell COX-2 by non-steroidal anti-inflammatory drugs suppresses ␣ V ␤ 3 -(but not ␣ 5 ␤ 1 -) dependent Rac activation, endothelial cell spreading, migration, and angiogenesis (Dormond, O., Foletti, A., Paroz, C., and Ruegg, C. (2001) Nat. Med. 7, 1041-1047). Here we investigated the role of the COX-2 metabolites PGE 2 and TXA2 in regulating human umbilical vein endothelial cell (HUVEC) adhesion and spreading. We report that PGE 2 accelerated ␣ V ␤ 3 -mediated HUVEC adhesion and promoted Rac activation and cell spreading, whereas the TXA2 agonist U46619 retarded adhesion and inhibited spreading. We show that the cAMP level and the cAMP-regulated protein kinase A (PKA) activity are critical mediators of these PGE 2 effects. ␣ V ␤ 3 -mediated adhesion induced a transient COX-2-dependent rise in cAMP levels, whereas the cellpermeable cAMP analogue 8-brcAMP accelerated adhesion, promoted Rac activation, and cell spreading in the presence of the COX-2 inhibitor NS-398. Pharmacological inhibition of PKA completely blocked ␣ V ␤ 3 -mediated adhesion. A constitutively active Rac mutant (L61Rac) rescued ␣ V ␤ 3 -dependent spreading in the presence of NS398 or U46691, but did not accelerate adhesion, whereas a dominant negative Rac mutant (N17Rac) suppressed spreading without affecting adhesion. ␣ 5 ␤ 1 -mediated HU-VEC adhesion, Rac activation, and spreading were not affected by PGE 2 , U46691, 8-brcAMP, or the inhibition of PKA. In conclusion, these results demonstrate that PGE 2 accelerates ␣ V ␤ 3 -mediated endothelial cell adhesion through cAMP-dependent PKA activation and induces ␣ V ␤ 3 -dependent spreading via cAMP-and PKA-dependent Rac activation and may contribute to the further understanding of the regulation of vascular integrins ␣ V ␤ 3 by COX-2/PGE 2 during tumor angiogenesis and inflammation.Tumor angiogenesis, i.e. the formation of new blood vessels in response to angiogenic stimuli, promotes tumor progression by stimulating tumor cell survival, tumor invasion, and metastasis formation (1). Many molecules involved in mediating or regulating angiogenesis have been identified (2). They include growth factors (i.e. vascular endothelial growth factors, VEGF) 1 and their cell surface receptors, matrix-degrading enzymes (e.g. matrix metalloproteinases), vascular remodeling ligands, and receptors (i.e. angiopoietins and Tie receptors) and adhesion receptors of the integrin and cadherin families. Integrins are the main receptors for extracellular matrix proteins and consist of two non-covalently associated ␣ and ␤ subunits (3). Integrin ligand binding affinity and adhesion-promoting activity are regulated by intracellular events ("inside out" signaling) (4). Upon ligand binding, integrins rapidly cluster and recruit structural (e.g. ␣-actinin, talin, vinculin) and signaling (e.g. focal adhesion kinase, paxillin, c-Src) proteins to form characteristic structures called focal contacts or focal adhesions (5). Integrins and focal adhesions propagate tensional ...

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Protein Kinase A Regulates Rac and Is Required for the Growth Factor-stimulated Migration of Carcinoma Cells

Cited by 128 publications

References 39 publications

Direct cAMP Signaling through G-Protein-Coupled Receptors Mediates Growth Cone Attraction Induced by Pituitary Adenylate Cyclase-Activating Polypeptide

Direct cAMP Signaling through G-Protein-Coupled Receptors Mediates Growth Cone Attraction Induced by Pituitary Adenylate Cyclase-Activating Polypeptide

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

Prostaglandin E2 Promotes Integrin αVβ3-dependent Endothelial Cell Adhesion, Rac-activation, and Spreading through cAMP/PKA-dependent Signaling

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