Interactions of Drebrin and Gephyrin with Profilin

Mammoto, Akiko; Sasaki, Takuya; Asakura, Takeshi; Hotta, Ikuko; Imamura, Hiroshi; Takahashi, Kazuo; Matsuura, Yoshiharu; Shirao, Tomoaki; Takai, Yoshimi

doi:10.1006/bbrc.1997.8068

Cited by 132 publications

(102 citation statements)

References 27 publications

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“…However, the binding of other ligands via the poly(L-proline) binding site in profilin is also necessary as revealed by rescue experiments in yeast (31) and Dictyostelium (32). Much as profilin can sequester actin monomers, the interaction with ligands such as Arp2͞3 complex (33), VASP (14), Mena (13), drebrin, gephyrin (16), SMN (17), and others may serve to sequester these ligands until they are needed to trigger a specific cellular process. Because the viability of profilin I null embryos is so limited, we speculate that leaving all of the profilin I ligands unlocked could be one cause for the cell lethal phenotype.…”

Section: Discussionmentioning

confidence: 99%

“…Part of the complication is that profilin interacts not only with actin but also with a large number of ligands such as Mena (13), VASP (14), dynamin I (15), gephyrin (16), and SMN (17), and that this ligand binding might be an important aspect of profilin function. The promiscuity of profilin for a plethora of signaling molecules provides links between a variety of cellular processes and actin remodeling, but it also complicates the interpretation of profilin's function in vivo.…”

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confidence: 99%

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Profilin I is essential for cell survival and cell division in early mouse development

Witke

Sutherland²,

Sharpe³

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

218

184

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Profilins are thought to play a central role in the regulation of de novo actin assembly by preventing spontaneous actin polymerization through the binding of actin monomers, and the adding of monomeric actin to the barbed actin-filament ends. Other cellular functions of profilin in membrane trafficking and lipid based signaling are also likely. Binding of profilins to signaling molecules such as Arp2͞3 complex, Mena, VASP, N-WASP, dynamin I, and others, further implicates profilin and actin as regulators of diverse motile activities. In mouse, two profilins are expressed from two distinct genes. Profilin I is expressed at high levels in all tissues and throughout development, whereas profilin II is expressed in neuronal cells. To examine the function of profilin I in vivo, we generated a null profilin I (pfn1 ko ) allele in mice. Homozygous pfn1 ko/ko mice are not viable. Pfn1 ko/ko embryos died as early as the two-cell stage, and no pfn1 ko/ko blastocysts were detectable. Adult pfn1 ko/wt mice show a 50% reduction in profilin I expression with no apparent impairment of cell function. However, pfn1 ko/wt embryos have reduced survival during embryogenesis compared with wild type. Although weakly expressed in early embryos, profilin II cannot compensate for lack of profilin I. Our results indicate that mouse profilin I is an essential protein that has dosage-dependent effects on cell division and survival during embryogenesis.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Profilin I is essential for cell survival and cell division in early mouse development

Witke

Sutherland²,

Sharpe³

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

218

184

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“…85 Endogenous profilin and Mena were found to colocalize with gephyrin in the inhibitory synapses of spinal cord neurons, and were enriched in gephyrin-rich domains of the neuronal plasma membrane. 85 Gephyrin and profilin 1 were shown to form a complex, 86 but via an unexpected binding mode that required the E domain of gephyrin and the actin/ PIP 2 -binding site of profilins (Giesemann et al, 85 but also see Bausen et al 87 ). A study examining the potential impact of these multipartite interactions on the function of gephyrin showed that cytochalasin D (an actin-depolymerizing agent) had differential effects on gephyrin clusters that were lost following cytochalasin D treatment of immature cultures but not following the same treatment of more mature cultures.…”

Section: Collybistinmentioning

confidence: 99%

Gephyrin: a central GABAergic synapse organizer

2015

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Gephyrin is a central element that anchors, clusters and stabilizes glycine and γ-aminobutyric acid type A receptors at inhibitory synapses of the mammalian brain. It self-assembles into a hexagonal lattice and interacts with various inhibitory synaptic proteins. Intriguingly, the clustering of gephyrin, which is regulated by multiple posttranslational modifications, is critical for inhibitory synapse formation and function. In this review, we summarize the basic properties of gephyrin and describe recent findings regarding its roles in inhibitory synapse formation, function and plasticity. We will also discuss the implications for the pathophysiology of brain disorders and raise the remaining open questions in this field.

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“…Indeed, enhancement in profilin accumulation at contacts with infected cells is observed when this mutant, with no drebrin profilin-binding region, is overexpressed in target cells. Profilin accumulation at these areas might be the consequence of profilin interaction with G-actin and/or with other proteins known as profilin partners (39). Therefore, drebrin limits profilin local concentration and stabilizes actin polymerization.…”

Section: Discussionmentioning

confidence: 99%

“…Drebrin appears to regulate F-actin by inducing structural changes in the microfilaments (33,34) and by competition with other actin-binding proteins such as fascin (37), ␣-actinin, and tropomyosin (36). Moreover, drebrin regulates the recruitment of other actin-regulatory proteins such as myosin, gelsolin, and profilin through direct association with them (38,39). We previously showed that interaction between drebrin and CXCR4 occurs at the T lymphocyte membrane and this molecular association is enhanced during superantigen presentation at the immunological synapse (35).…”

mentioning

confidence: 99%

Actin-binding Protein Drebrin Regulates HIV-1-triggered Actin Polymerization and Viral Infection

Gordon-Alonso

Rocha-Perugini

Álvarez

et al. 2013

Journal of Biological Chemistry

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Background: Drebrin binds to F-actin and CXCR4 in T cells. Thus, it is a potential candidate for the modulation of HIV-1 infection. Results: Drebrin and CXCR4 accumulate at viral attachment areas. Drebrin knockdown decreases F-actin polymerization, and increases local profilin accumulation and HIV-1 infection. Conclusion: Drebrin inhibits HIV-1 entry by stabilizing HIV-1-triggered F-actin polymerization. Significance: Modulation of actin dynamics differentially regulates each viral step for an effective viral infection. HIV-1 contact with target cells triggers F-actin rearrangements that are essential for several steps of the viral cycle. Successful HIV entry into CD4؉ T cells requires actin reorganization induced by the interaction of the cellular receptor/co-receptor complex CD4/CXCR4 with the viral envelope complex gp120/gp41 (Env).In this report, we analyze the role of the actin modulator drebrin in HIV-1 viral infection and cell to cell fusion. We show that drebrin associates with CXCR4 before and during HIV infection. Drebrin is actively recruited toward cellvirus and Env-driven cell to cell contacts. After viral internalization, drebrin clustering is retained in a fraction of the internalized particles. Through a combination of RNAi-based inhibition of endogenous drebrin and GFP-tagged expression of wild-type and mutant forms, we establish drebrin as a negative regulator of HIV entry and HIV-mediated cell fusion. Down-regulation of drebrin expression promotes HIV-1 entry, decreases F-actin polymerization, and enhances profilin local accumulation in response to HIV-1. These data underscore the negative role of drebrin in HIV infection by modulating viral entry, mainly through the control of actin cytoskeleton polymerization in response to HIV-1.Human immunodeficiency virus (HIV)-1 entry requires fusion between the viral envelope and the plasma membrane of the target cell (1). This process is mediated by the viral envelope glycoprotein complex gp120/gp41 (Env), 5 which interacts first with CD4 and then with a co-receptor, one of the chemokine receptors CCR5 or CXCR4 (2, 3).For the viral and cellular membranes to fuse, a critical number of gp120-CD4/coreceptor engagements are needed to establish an energetically productive fusion pore (4). HIV-1 can also be transmitted from infected to uninfected cells through cell to cell contacts, called virological synapses because of their similarities to the immunological synapse (5). As an example, CD4 and CXCR4 recruitment (6 -8) and local actin polymerization take place in both processes (6, 9 -11). Receptor clustering is regulated by two main factors: 1) insertion into specific membrane domains by lateral membrane receptor interactions (12) such as lipid rafts (13) or tetraspanin-enriched microdomains (14 -17); and 2) actin remodeling (6, 18 -20). This phenomenon is well illustrated by experiments in which HIV-1 contact induces CD4 and CXCR4 capping at the plasma membrane of target CD4 ϩ T lymphocytes (21,22). Receptor capping requires the formation of a subcortical...

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Interactions of Drebrin and Gephyrin with Profilin

Cited by 132 publications

References 27 publications

Profilin I is essential for cell survival and cell division in early mouse development

Profilin I is essential for cell survival and cell division in early mouse development

Gephyrin: a central GABAergic synapse organizer

Actin-binding Protein Drebrin Regulates HIV-1-triggered Actin Polymerization and Viral Infection

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