Serine phosphorylation differentially affects RhoA binding to effectors: Implications to NGF-induced neurite outgrowth

Nusser, Nóra; Gosmanova, Elvira O.; Makarova, Natalia; Fujiwara, Yuko; Yang, Linda; Guo, Fukun; Luo, Yuan; Zheng, Yi; Tigyi, Gábor

doi:10.1016/j.cellsig.2005.06.010

Cited by 52 publications

(48 citation statements)

References 42 publications

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“…This raises the possibility of a novel level of RhoA regulation in response to myelin inhibitors in which the focus has primarily been on the ability of MAIs to convert RhoA to the GTP-bound form Niederost et al, 2002;Fournier et al, 2003). This idea is consistent with finding that RhoA is phosphorylated at Ser188 by protein kinase A and that RhoA phosphorylation modifies its binding to its endogenous inhibitor, Rho guanine nucleotide dissociation factor (Ellerbroek et al, 2003;Nusser et al, 2006). CRMP4 is subject to phosphorylation by glycogen synthase kinase-3␤ and dephosphorylation by protein phosphatase 2A (Hill et al, 2006), and it is reasonable to hypothesize that phosphorylation alters its binding properties based on similarities to CRMP2 (Uchida et al, 2005).…”

Section: Dynamics Of the Crmp4b-rhoa Interactionsupporting

confidence: 74%

Identification of CRMP4 as a Convergent Regulator of Axon Outgrowth Inhibition

Alabed¹,

Pool²,

Tone³

et al. 2007

J. Neurosci.

131

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Myelin-associated inhibitors (MAIs) and chondroitin sulfate proteoglycans (CSPGs) contribute to failed regeneration after neuronal injury. MAIs and CSPGs stimulate intracellular signals including the activation of RhoA and Rho kinase to block axonal extension through targeted modifications to the cytoskeleton. RhoA and ROCK are promising targets for therapeutic intervention to promote CNS repair; however, their ubiquitous expression will limit the specificity of drugs targeted to these molecules. We have identified the cytosolic phosphoprotein CRMP4b (collapsin-response mediator protein 4b) as a protein that physically and functionally interacts with RhoA to mediate neurite outgrowth inhibition. Short interfering RNA-mediated knockdown of CRMP4 promotes neurite outgrowth on myelin substrates, indicating a critical role for CRMP4 in neurite outgrowth inhibition. Disruption of CRMP4b-RhoA binding with a competitive inhibitor attenuates neurite outgrowth inhibition on myelin and aggrecan substrates. Stimulation of neuronal growth cones with Nogo leads to colocalization of CRMP4b and RhoA at discrete regions within the actin-rich central and peripheral domains of the growth cone, indicative of a potential function in cytoskeletal rearrangements during neurite outgrowth inhibition. Together, these data indicate that a RhoA-CRMP4b complex forms in response to inhibitory challenges in the growth cone environment and regulates cytoskeletal dynamics at distinct sites necessary for axon outgrowth inhibition. Competitive inhibition of CRMP4b-RhoA binding suggests a novel, highly specific therapeutic avenue for promoting regeneration after CNS injury.

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Section: Dynamics Of the Crmp4b-rhoa Interactionsupporting

confidence: 74%

Identification of CRMP4 as a Convergent Regulator of Axon Outgrowth Inhibition

Alabed¹,

Pool²,

Tone³

et al. 2007

J. Neurosci.

131

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“…Similar correlation was reported in bovine aortic and rat muscle cells (Gudi et al, 2002;Krepinsky et al, 2003). However, in certain cell types, such as PC12 cells, this assay may not reflect changes in RhoA activity induced by PKGmediated serine 188 phosphorylation because in those cells phosphorylated RhoA can still interact with rhotekin while losing its ability to interact with other downstream effectors (Nusser et al, 2006).…”

Section: Discussionsupporting

confidence: 64%

The ADMA/DDAH pathway is a critical regulator of endothelial cell motility

Wójciak-Stothard

Torondel

Tsang

et al. 2007

Journal of Cell Science

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“…4,19 We found that 6xHis-RhoC-R188S is a PKA substrate in vitro, therefore a potential mechanism behind its diminished cell contractility phenotype, membrane association, and GTPloading could involve acquisition of phospho-Ser188 inhibition of ROCK binding and/or increased RhoGDIa inhibition and extraction from membranes.…”

Section: Discussionmentioning

confidence: 99%

“…[16][17][18] It has been suggested that RhoA Ser188 phosphorylation impedes engagement of the key downstream effector Rho-associated kinase and promotes binding of the intracellular inhibitor RhoGDI concomitant with increased extraction of the GTPase from plasma membranes. 4,19 Moreover, it is likely the addition of a negatively charged group to the end of the PBR facilitates RhoA extraction by destabilizing its electrostatic binding to the inner plasma membrane surface.…”

Section: Introductionmentioning

confidence: 99%

Arg188 drives RhoC membrane binding

et al. 2016

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RhoA and RhoC GTPases are 92% identical but demonstrate unique regulation and function. Phosphorylation of Ser188 has widely been reported to inhibit RhoA activity. RhoC possesses Arg188 in place of Ser188 but retains a canonical upstream PKA recognition sequence. We report here that RhoC-R188S was a PKA substrate in vitro and exhibited less GTP loading compared to wild-type RhoC when expressed in cells. Transiently expressed RhoC was found to be significantly more membrane associated than RhoA. Membrane association of RhoC-R188S and RhoC-R188A were similar to each other and wild-type RhoA, suggesting that Arg188 directly promotes RhoC membrane binding. The positive influence of Arg188 on RhoC membrane association was evident in a constitutively active (Q63L) background. In accordance, RhoA-S188R was significantly more membrane associated than either RhoA or RhoA-S188A. Altogether, these data suggest that swapping residue 188 identity effectively flips the membrane binding profile of wild-type RhoA and RhoC through positive arginine contribution rather than negative phosphoserine regulation.

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Serine phosphorylation differentially affects RhoA binding to effectors: Implications to NGF-induced neurite outgrowth

Cited by 52 publications

References 42 publications

Identification of CRMP4 as a Convergent Regulator of Axon Outgrowth Inhibition

Identification of CRMP4 as a Convergent Regulator of Axon Outgrowth Inhibition

The ADMA/DDAH pathway is a critical regulator of endothelial cell motility

Arg188 drives RhoC membrane binding

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