Cdc42 induces filopodia by promoting the formation of an IRSp53:Mena complex

Krugmann, Sonja; Jordens, Ingrid; Gevaert, Kris; Driessens, M. H. E.; Vandekerckhove, Joël; Hall, Alan

doi:10.1016/s0960-9822(01)00506-1

Cited by 369 publications

(459 citation statements)

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“…Although proline-rich peptides may supply espins with another way to increase the local concentration of actin monomer, profilin-espin interactions have not yet been documented in situ, and known espin activities such as microvillar PAB elongation and WH2 domain-mediated actin bundle assembly do not appear to require the proline-rich peptides [13,14]. IRSp53 is an SH3 domain-containing scaffolding protein that links Rac1 and Cdc42 small GTPases to actin cytoskeletal regulators, such as WAVE2 and Mena [74,75]. IRSp53 was identified as an espin ligand by yeast two-hybrid screening [15].…”

Section: Binding Pip2 and Ligands For Proline-rich Peptidesmentioning

confidence: 99%

“…Accordingly, the espin 3 isoforms, which lack this proline-rich peptide, do not bind the IRSp53 SH3 domain [4]. Although implicated in actin cytoskeletal regulation in lamellipodia, ruffles, filopodia and dendritic spines [15,[74][75][76], evidence linking IRSp53 to stereocilia and microvilli is currently lacking. It is possible that the espin proline-rich peptides interact with other SH3 domain-containing scaffolding proteins in stereocilia and microvilli.…”

Section: Binding Pip2 and Ligands For Proline-rich Peptidesmentioning

confidence: 99%

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Espins and the actin cytoskeleton of hair cell stereocilia and sensory cell microvilli

Sekerková

Zheng

Loomis

et al. 2006

Cell. Mol. Life Sci.

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The espins are novel actin-bundling proteins that are produced in multiple isoforms from a single gene. They are present at high concentration in the parallel actin bundle of hair cell stereocilia and are the target of deafness mutations in mice and humans. Espins are also enriched in the microvilli of taste receptor cells, solitary chemoreceptor cells, vomeronasal sensory neurons and Merkel cells, suggesting that espins play important roles in the microvillar projections of vertebrate sensory cells. Espins are potent actin-bundling proteins that are not inhibited by Ca 2+ . In cells, they efficiently elongate parallel actin bundles and, thereby, help determine the steady-state length of microvilli and stereocilia. Espins bind actin monomer via their WH2 domain and can assemble actin bundles in cells. Certain espin isoforms can also bind phosphatidylinositol 4,5-bisphosphate, profilins or SH3 proteins. These biological activities distinguish espins from other actin-bundling proteins and may make them well-suited to sensory cells. KeywordsEspin; actin; hair cell; stereocilia; microvilli; sensory; deafness; taste The stereocilia and microvilli of vertebrate sensory cells and their actinbundling proteinsMany classes of vertebrate sensory cells detect chemical or mechanical stimuli through microvilli or their derivatives, such as stereocilia. These relatively long-lived, fingerlike specializations of the plasma membrane are built around a common cytoskeletal element -the parallel actin bundle (PAB) [1]. PABs consist of tightly packed collections of actin filaments cross-linked by actin-bundling proteins. The filaments are aligned along their longitudinal axis and display a uniform polarity with respect to their preferred ends for actin monomer addition, which in microvilli and stereocilia is positioned at the distal tip. The PAB displays hallmarks of a supramolecular scaffold that determines the placement, dimensions, flexibility and signaling properties of microvilli and stereocilia. Although filopodia also contain a PAB at their core and are believed to sense the local environment, they are considerably more dynamic and differ significantly from microvilli and stereocilia in their molecular composition and biogenesis [2].

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Section: Binding Pip2 and Ligands For Proline-rich Peptidesmentioning

confidence: 99%

Section: Binding Pip2 and Ligands For Proline-rich Peptidesmentioning

confidence: 99%

Espins and the actin cytoskeleton of hair cell stereocilia and sensory cell microvilli

Sekerková

Zheng

Loomis

et al. 2006

Cell. Mol. Life Sci.

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“…In fibroblasts, IRSp53 serves as an adaptor between cdc42 and mena. Together this complex stimulates filopodia elaboration (Krugmann et al 2001).…”

Section: Rho Gtpases: Organizers Of Actin Structuresmentioning

confidence: 99%

Signaling mechanisms that regulate actin‐based motility processes in the nervous system

Meyer

Feldman

2002

Journal of Neurochemistry

172

108

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Actin-based motility is critical for nervous system development. Both the migration of neurons and the extension of neurites require organized actin polymerization to push the cell membrane forward. Numerous extracellular stimulants of motility and axon guidance cues regulate actin-based motility through the rho GTPases (rho, rac, and cdc42). The rho GTPases reorganize the actin cytoskeleton, leading to stress fiber, filopodium, or lamellipodium formation. The activity of the rho GTPases is regulated by a variety of proteins that either stimulate GTP uptake (activation) or hydrolysis (inactivation). These proteins potentially link extracellular signals to the activation state of rho GTPases. Effectors downstream of the rho GTPases that directly influence actin polymerization have been identified and are involved in neurite development.The Arp2/3 complex nucleates the formation of new actin branches that extend the membrane forward. Ena/VASP proteins can cause the formation of longer actin filaments, characteristic of growth cone actin morphology, by preventing the capping of barbed ends. Actin-depolymerizing factor (ADF)/cofilin depolymerizes and severs actin branches in older parts of the actin meshwork, freeing monomers to be re-incorporated into actively growing filaments. The signaling mechanisms by which extracellular cues that guide axons to their targets lead to direct effects on actin filament dynamics are becoming better understood. Keywords: actin-depolymerizing factor (ADF)/cofilin, actinrelated protein Arp2/3, ena/VASP, LIM kinase, rho GTPase.

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“…WASP interacts directly with CDC42 and activates the ARP2-ARP3 (ARP2/3) complexes to catalyze actin nucleation and polymerization (Miki et al, 1996). Other proteins such as IRSp53 (BAIAP2) and the diaphanous-related-formin DRF3 (DIAPH3) have also been implicated in promoting filopodia formation downstream of CDC42 (Govind et al, 2001;Krugmann et al, 2001;Peng et al, 2003). The WAVE proteins act downstream of RAC1 to modulate the formation of lamellipodia, using IRSp53 as an intermediate (Miki et al, 1998;Miki et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Functional interactions between phosphatase POPX2 and mDia modulate RhoA pathways

Xie

Tan

Wee

et al. 2008

Journal of Cell Science

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Rho GTPases and their downstream effectors regulate changes in the actin cytoskeleton that underlie cell motility and adhesion. They also participate, with RhoA, in the regulation of gene transcription by activating serum response factor (SRF)-mediated transcription from the serum response element (SRE). SRF-mediated transcription is also promoted by several proteins that regulate the polymerization or stability of actin. We have previously identified a family of PP2C phosphatases, POPXs, which can dephosphorylate the CDC42/RAC-activated kinase PAK and downregulate its enzymatic and actin cytoskeletal activity. We now report that POPX2 interacts with the formin protein mDia1 (DIAPH1). This interaction is enhanced when mDia1 is activated by RhoA.The binding of POPX2 to mDia1 or to an mDia-containing complex greatly decreases the ability of mDia1 to activate transcription from the SRE. We propose that the interaction between mDia1 and POPX2 (PPM1F) serves to regulate both the actin cytoskeleton and SRF-mediated transcription, and to link the CDC42/RAC1 pathways with those of RhoA. Supplementary material available online at

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Cdc42 induces filopodia by promoting the formation of an IRSp53:Mena complex

Abstract: We conclude that the interaction of Cdc42 with the partial CRIB motif of IRSp53 relieves an intramolecular, autoinhibitory interaction with the N terminus, allowing the recruitment of Mena to the IRSp53 SH3 domain. This IRSp53:Mena complex initiates actin filament assembly into filopodia.

Cited by 369 publications

References 44 publications

Espins and the actin cytoskeleton of hair cell stereocilia and sensory cell microvilli

Espins and the actin cytoskeleton of hair cell stereocilia and sensory cell microvilli

Signaling mechanisms that regulate actin‐based motility processes in the nervous system

Functional interactions between phosphatase POPX2 and mDia modulate RhoA pathways

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