ERK1/2 phosphorylate GEF-H1 to enhance its guanine nucleotide exchange activity toward RhoA

Fujishiro, Shuh-hei; Tanimura, Susumu; Mure, Shogo; Kashimoto, Yuji; Watanabe, Kazushi; Kohno, Michiaki

doi:10.1016/j.bbrc.2008.01.066

Cited by 67 publications

(73 citation statements)

References 20 publications

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“…can be phosphorylated by ERK at Thr-678, and we found that this phosphorylation is necessary for its TNF␣-induced activation in tubular cells (19,24). Consistent with our previous finding, complement C5b-9 activated ERK in rat GEC, and this activation paralleled GEF-H1 activation (Fig.…”

Section: Complement-mediated Gef-h1 Activation Is Mediated By Erk Butsupporting

confidence: 91%

“…We found that complement-induced GEF-H1 activation is dependent on ERK. Similar ERK-dependent activation of GEF-H1 toward RhoA induced by TNF␣ was described in renal tubular epithelial cells (LLC-PK1 and MDCK cells) (19,24). However, unlike in these cells, complement-induced GEF-H1 activation was independent of the EGF receptor activation (38), suggesting a different mechanism for ERK activation.…”

Section: Discussionmentioning

confidence: 61%

“…The plasmids pLKO.1-TRC cloning vector, pMD2.G, psPAX2, and lentiviral shRNA GEF-H1 were from Addgene (Cambridge, MA) (23). The GFP-tagged wild type (WT) GEF-H1 and the point mutant GEF-H1-T678A were gifts from Dr. M. Kohno (24).…”

Section: Methodsmentioning

confidence: 99%

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Role of Guanine Nucleotide Exchange Factor-H1 in Complement-mediated RhoA Activation in Glomerular Epithelial Cells

Mouawad

Aoudjit

Jiang

et al. 2014

Journal of Biological Chemistry

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Background: Disruption of the actin cytoskeleton-dependent structural integrity of glomerular epithelial cells (GEC) leads to glomerular dysfunction. Results: We have identified molecular mechanisms through which the injury-causing complement complex induces cytoskeletal changes in GEC. Conclusion: Complement-induced activation of the ERK/GEF-H1/RhoA pathway protects GEC from cell death. Significance: This study furthers our understanding of mechanisms underlying GEC foot process effacement and functional impairment in immune mediated glomerular diseases.

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Section: Complement-mediated Gef-h1 Activation Is Mediated By Erk Butsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 61%

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Role of Guanine Nucleotide Exchange Factor-H1 in Complement-mediated RhoA Activation in Glomerular Epithelial Cells

Mouawad

Aoudjit

Jiang

et al. 2014

Journal of Biological Chemistry

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“…While the significance remains unclear, Lfc is phosphorylated by PAK kinases (10,59) at several sites and interacts with 14-3-3 proteins in a phosphorylation-specific manner (59). Moreover, Lfc recently was shown to be phosphorylated and inhibited by Aurora A/B and Cdk1/Cyclin B during mitosis (8) and activated by ERK1/2 (24).…”

mentioning

confidence: 99%

Modulation of Rho Guanine Exchange Factor Lfc Activity by Protein Kinase A-Mediated Phosphorylation

Meiri

Greeve

Brunet

et al. 2009

Molecular and Cellular Biology

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Lfc is a guanine nucleotide exchange factor (GEF) for Rho that demonstrates an unusual ability to associate with microtubules. While several phosphorylated residues have been detected in the Lfc polypeptide, the mechanism(s) by which phosphorylation regulates the exchange activity of Lfc remains unclear. We confirm that Lfc is a phosphorylated protein and demonstrate that 14-3-3 interacts directly and in a phosphorylationdependent manner with Lfc. We identify AKAP121 as an Lfc-binding protein and show that Lfc is phosphorylated in an AKAP-dependent manner by protein kinase A (PKA). Forskolin treatment induced 14-3-3 binding to Lfc and suppressed the exchange activity of wild-type Lfc on RhoA. Importantly, a mutant of Lfc that is unable to associate with 14-3-3 proteins was resistant to inhibition by forskolin. Tctex-1, a dynein motor light chain, binds to Lfc in a competitive manner with 14-3-3.RhoGTPases are key regulators of transcription, cell cycle progression, and the organization of the microtubule and actin cytoskeletons. By cycling between active GTP-bound and inactive GDP-coupled states, these enzymes behave as molecular switches. The activation state of RhoGTPases is governed by the balance between the activities of GTPase-activating proteins (GAPs) and guanine exchange factors (GEFs). While the hydrolysis of GTP to GDP by RhoGTPases is enhanced by RhoGAPs, RhoGEFs mediate the exchange of GDP for GTP.Characterized by tandem Dbl homology (DH) and pleckstrin homology (PH) domains, the Dbl family represents the largest group of RhoGEFs. The DH domain mediates binding to inactive GTPases and catalyzes the exchange of GDP for GTP. The role of the PH domain is less well defined and may facilitate the interaction of some RhoGEFs with the plasma membrane and cooperate with the DH domain in activating RhoGTPases (45). In addition to the DH-PH core, many RhoGEFs also possess extended N and/or C termini with negative regulatory functions. Thus, a number of RhoGEFs are constitutively activated by N-or C-terminal truncation (21,34,36). Moreover, N and C termini frequently mediate interactions with other proteins, thereby functioning to integrate several signaling pathways. The regulator of G protein signaling (RGS) homology domain-containing RhoGEFs, p115RhoGEF (35), LARG (50), and PDZ-RhoGEF (25), for instance, can bind directly to and be activated by the G␣ subunits of heterotrimeric G proteins. Nearly 40% of human Dbl family RhoGEFs contain C-terminal PDZ binding motifs, suggesting that interactions with PDZ domain-containing proteins represent a common mechanism for controlling RhoGEF localization and activity (26). A number of RhoGEFs possess unrelated domains in addition to the tandem DH-PH core, thus allowing the enzymes to nucleate unique signaling networks. For instance, mammalian Son-of-sevenless (Sos) can coordinate the activities of both Rac and Ras by virtue of both a tandem DH-PH cassette and a RasGEF homology domain (12, 42). Kalirin and Trio have separate functional GEF domains for Rho and Rac in ad...

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“…It is worth noting that ERK1/2-dependent phosphorylation has also been previously observed on GEF-H1 and ARHGAP26, both of which regulate RhoA. 29,30 These multiple related ERK 1/2 substrates suggest that crosstalk between ERK signaling and the Rho GTPases could occur at several points, both upand downstream from the Rho GTPases themselves. It will be interesting to determine the functional significance of these phosphorylation sites on related proteins in this network: does phosphorylation on any site lead to a small change, with the ensemble phosphorylation then driving a much larger overall effect, or is phosphorylation of one of these sites sufficient to induce a significant phenotypic effect, with the multiple different sites then representing a fail-safe mechanism?…”

Section: Potential Applications For Chemical Geneticsmentioning

confidence: 66%

Expanding applications of chemical genetics in signal transduction

Carlson

White

2012

Cell Cycle

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Chemical genetics represents an expanding collection of techniques applied to a variety of signaling processes. These techniques use a combination of chemical reporters and protein engineering to identify targets of a signaling enzyme in a global and non-directed manner without resorting to hypothesisdriven candidate approaches. In the last year, chemical genetics has been applied to a variety of kinases, revealing a much broader spectrum of substrates than had been appreciated. Here, we discuss recent developments in chemical genetics, including insights from our own proteomic screen for substrates of the kinase ERK2. These studies have revealed that many kinases have overlapping substrate specificity, and they often target several proteins in any particular downstream pathway. It remains to be determined whether this configuration exists to provide redundant control, or whether each target contributes a fraction of the total regulatory effect. From a general perspective, chemical genetics is applicable in principle to a broad range of posttranslational modifications (PTMs), most notably, methylation and acetylation, although many challenges remain in implementing this approach. Recent developments in chemical reporters and protein engineering suggest that chemical genetics will soon be a powerful tool for mapping signal transduction through these and other PTMs.

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ERK1/2 phosphorylate GEF-H1 to enhance its guanine nucleotide exchange activity toward RhoA

Cited by 67 publications

References 20 publications

Role of Guanine Nucleotide Exchange Factor-H1 in Complement-mediated RhoA Activation in Glomerular Epithelial Cells

Role of Guanine Nucleotide Exchange Factor-H1 in Complement-mediated RhoA Activation in Glomerular Epithelial Cells

Modulation of Rho Guanine Exchange Factor Lfc Activity by Protein Kinase A-Mediated Phosphorylation

Expanding applications of chemical genetics in signal transduction

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