Dual Requirement for Rho and Protein Kinase C in Direct Activation of Phospholipase D1 Through G Protein-coupled Receptor Signaling

Du, Guangwei; Altshuller, Yelena M.; Kim, Yong; Han, Jung Min; Ryu, Sung Ho; Morris, Andrew J.; Frohman, Michael A.

doi:10.1091/mbc.11.12.4359

Cited by 101 publications

(84 citation statements)

References 42 publications

(56 reference statements)

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“…Exton et al suggested that RhoA might activate PLD by direct interaction, since RhoA can activate PLD in vitro (Bae et al, 1998). Although the action of RhoA on PLD1 in vivo has been proposed to take place through indirect pathways (Schmidt et al, 1999), Frohman's group suggested that direct stimulation of PLD1 in vivo by RhoA is critical for significant PLD1 activation (Du et al, 2000). Our studies also revealed that PLD1 associates with the active form of RhoA in vivo.…”

Section: Discussionsupporting

confidence: 57%

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Phosphorylation of phospholipase D1 and the modulation of its interaction with RhoA by cAMP-dependent protein kinase

Jang

Lee²,

Park³

et al. 2004

Exp Mol Med

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A bstractAgents that elevate cellular cAM P are know n to inhibit the activation of phospholipase D (PLD). W e investigated w hether PLD can be phosphorylated by cAM P-dependent protein kinase (PKA) and PKA-m ediated phosphorylation affects the interaction betw een PLD and RhoA, a m em brane regulator of PLD. PLD1, but not PLD2 w as found to be phosphorylated in vivo by the treatm ent of dibutyryl cA M P (dbcA M P) and in vitro by PKA. PKA inhibitor (KT5720) abolished the dbcAM P-induced phosphorylation of PLD1, but dibutyryl cGMP (dbcGMP) failed to phosphorylate PLD1. The association betw een PLD1 and Val14RhoA in an im m unoprecipitation assay w as abolished by both dbcAM P and dbcG M P. M oreover, RhoA but not PLD1 w as dissociated from the m em brane to the cytosolic fraction in dbcAM P-treated cells. These results suggest that both PLD1 and RhoA are phosphorylated by PKA and the interaction betw een PLD1 and RhoA is inhibited by the phosphorylation of RhoA rather than by the phosphorylation of PLD1.

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Section: Discussionsupporting

confidence: 57%

“…Previous studies have demonstrated that the effector region (switch I) of RhoA interacts with the C-terminus of human PLD1 (Bae et al, 1998;Yamazaki et al, 1999;Cai and Exton, 2001). Moreover, in vivo studies have shown that PLD can be activated by the direct binding of RhoA (Du et al, 2000;Xie et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Phosphorylation of phospholipase D1 and the modulation of its interaction with RhoA by cAMP-dependent protein kinase

Jang

Lee²,

Park³

et al. 2004

Exp Mol Med

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“…Activation of hPLD1 by all Rho GTPases requires an initial GTP-dependent binding event mediated by switch I of the Rho protein. Several groups have shown that RhoA binds in a GTP-dependent manner to residues within the carboxyl-terminal region of PLD (residues 712-1074 in hPLD1) (13)(14)(15). Mutations in this region of PLD1 that block RhoA binding also block activation of PLD by RhoA, suggesting that this carboxylterminal region of PLD contains the switch I binding site for RhoA.…”

Section: Residues Of the Insert Helix Are Essential To Cdc42 Activatimentioning

confidence: 99%

Specificity of Rho Insert-mediated Activation of Phospholipase D1

Walker

Brown

2002

Journal of Biological Chemistry

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Members of the Rho subfamily of GTP-binding proteins regulate phospholipase D1 (PLD1) activity and signaling. In previous work, we demonstrated that binding of the Rho family member Cdc42 to PLD1 and the subsequent stimulation of its enzymatic activity are distinct events. Deletion of the insert helix from Cdc42 does not interfere with its switch I-mediated, GTP-dependent binding to PLD1 but inhibits Cdc42-stimulated PLD1 activity. To understand the mechanism of the insertmediated activation of PLD1 by Cdc42 and to develop reagents to study Cdc42-activated PLD1 in cellular signaling events, we have undertaken a mutational analysis of the Rho insert region of Cdc42 and examined the specificity of the insert helix requirement in the other Rho family members, RhoA and Rac1. Here, we identify a critical residue, serine 124, in the Cdc42 insert helix central to its activation mechanism. Further, we examine this activation mechanism with respect to other members of the Rho family and demonstrate that each Rho protein activates PLD by distinct mechanisms, potentially allowing for unique signaling outcomes in the cell.

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“…Other small GTPases such as RhoA, Rac1, and Cdc42 in the presence of GTP␥S directly associate with and stimulate PLD1 activity (5,6), as mutation of the Rho binding site on PLD1 prevents PLD1/ARF interaction (7,8). The Rho family of GTPases is also involved in indirect regulation of PLD1 enzymatic activity through stimulation of PI(4,5)P 2 kinase, Rho kinase, or by intracellular translocation of the PLD isoforms (9 -12).…”

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confidence: 99%

“…PLD2 localizes to cell membranes where its PH domain binds to PIP 2 (13,14). PLD2 can also be activated in intact cells by growth factors and agonists (8,15,16). On the other hand, Rac1 does not regulate the activity of the other PLD isoform, PLD2 (13,17).…”

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confidence: 99%

Evidence for Two CRIB Domains in Phospholipase D2 (PLD2) That the Enzyme Uses to Specifically Bind to the Small GTPase Rac2

Peng

Henkels

Mahankali

et al. 2011

Journal of Biological Chemistry

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Phospholipase D (PLD) and small GTPases are vital to cell signaling. We report that the Rac2 and the PLD2 isoforms exist in the cell as a lipase-GTPase complex that enables the two proteins to elicit their respective functionalities. A strong association between the two molecules was demonstrated by co-immunoprecipitation and was confirmed in living cells by FRET with CFP-Rac2 and YFP-PLD2 fluorescent chimeras. We have identified the amino acids in PLD2 that define a specific binding site to Rac2. This site is composed of two CRIB (Cdc42-and Racinteractive binding) motifs that we have named "CRIB-1" and "CRIB-2" in and around the PH domain in PLD2. Deletion mutants PLD2-⌬CRIB-1/2 negate co-immunoprecipitation with Rac2 and diminish the FRET signal in living cells. The PLD2-Rac2 association was further confirmed in vitro using affinity-purified recombinant proteins. Binding was saturable with an apparent K d of 3 nM and was diminished with PLD2-⌬CRIB mutants. Furthermore, PLD2 bound more efficiently to Rac2-GTP than to Rac2-GDP or to a GDP-constitutive Rac2-N17 mutant. Increasing concentrations of recombinant Rac2 in vitro and in vivo during cell adhesion inhibit PLD2. Conversely, Rac2 activity is increased in the presence of PLD2-WT but not in PLD2-⌬CRIB. We propose that in activated cells PLD2 affects Rac2 in an initial positive feedback, but as Rac2-GTP accumulates in the cell, this constitutes a "termination signal" leading to PLD2 inactivation.

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Dual Requirement for Rho and Protein Kinase C in Direct Activation of Phospholipase D1 Through G Protein-coupled Receptor Signaling

Cited by 101 publications

References 42 publications

Phosphorylation of phospholipase D1 and the modulation of its interaction with RhoA by cAMP-dependent protein kinase

Phosphorylation of phospholipase D1 and the modulation of its interaction with RhoA by cAMP-dependent protein kinase

Specificity of Rho Insert-mediated Activation of Phospholipase D1

Evidence for Two CRIB Domains in Phospholipase D2 (PLD2) That the Enzyme Uses to Specifically Bind to the Small GTPase Rac2

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