IRSp53: crossing the road of membrane and actin dynamics in the formation of membrane protrusions

Scita, Giorgio; Confalonieri, Stefano; Lappalainen, Pekka; Suetsugu, Shiro

doi:10.1016/j.tcb.2007.12.002

Cited by 243 publications

(286 citation statements)

References 75 publications

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“…Although lamellipodin and the inverse Bar-domain (IBAR)-protein insulin receptor substrate of 53 kDa (IRSp53) have been both implicated in clustering of VASP (16,35), the oligomerization state of lamellipodin is not yet clearly established. By contrast, IRSp53 is a Cdc42-regulated antiparallel dimer that contains C-terminal SH3 domains that interact with proline-rich regions of Ena/VASP proteins (36,37). Moreover, IRSp53 has been shown to cluster VASP by dynamic light scattering (16).…”

Section: Discussionmentioning

confidence: 99%

Distinct VASP tetramers synergize in the processive elongation of individual actin filaments from clustered arrays

Brühmann

Ushakov

Winterhoff

et al. 2017

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

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Ena/VASP proteins act as actin polymerases that drive the processive elongation of filament barbed ends in membrane protrusions or at the surface of bacterial pathogens. Based on previous analyses of fast and slow elongating VASP proteins by in vitro total internal reflection fluorescence microscopy (TIRFM) and kinetic and thermodynamic measurements, we established a kinetic model of Ena/VASP-mediated actin filament elongation. At steady state, it entails that tetrameric VASP uses one of its arms to processively track growing filament barbed ends while three G-actin-binding sites (GABs) on other arms are available to recruit and deliver monomers to the filament tip, suggesting that VASP operates as a single tetramer in solution or when clustered on a surface, albeit processivity and resistance toward capping protein (CP) differ dramatically between both conditions. Here, we tested the model by variation of the oligomerization state and by increase of the number of GABs on individual polypeptide chains. In excellent agreement with model predictions, we show that in solution the rates of filament elongation directly correlate with the number of free GABs. Strikingly, however, irrespective of the oligomerization state or presence of additional GABs, filament elongation on a surface invariably proceeded with the same rate as with the VASP tetramer, demonstrating that adjacent VASP molecules synergize in the elongation of a single filament. Additionally, we reveal that actin ATP hydrolysis is not required for VASP-mediated filament assembly. Finally, we show evidence for the requirement of VASP to form tetramers and provide an amended model of processive VASPmediated actin assembly in clustered arrays.actin | Ena/VASP | TIRF | cluster | formin

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Section: Discussionmentioning

confidence: 99%

Distinct VASP tetramers synergize in the processive elongation of individual actin filaments from clustered arrays

Brühmann

Ushakov

Winterhoff

et al. 2017

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

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“…Members of the IRSp53/MIM homology domain family are subdivided into two groups: the IRSp53-like members and the MIM-like members [3,4]. IRSp53-like proteins include IRSp53, IRTKS and BAIAP2L2 (FLJ22582), while the MIM-like proteins include two members, MIM and ABBA.…”

Section: Discussionmentioning

confidence: 99%

“…Members of this family have been shown to play an important role in the formation of plasma membrane protrusions [2]. IRSp53-like proteins contain a conserved IRSp53/MIM homology domain (IMD) at the N-terminus and a canonical SH3 domain near the C-terminus [3]. The IMD belongs to the larger family of Bin-amphyipysin-Rvs67 (BAR) domains, which can bundle actin filaments and induce membrane protrusions [4,5].…”

Section: Introductionmentioning

confidence: 99%

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Deficiency of IRTKS as an adaptor of insulin receptor leads to insulin resistance

et al. 2013

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IRTKS encodes a member of the IRSp53/MIM homology domain family, which has been shown to play an important role in the formation of plasma membrane protrusions. Although the phosphorylation of IRTKS occurs in response to insulin stimulation, the role of this protein in insulin signaling remains unknown. Here we show that IRTKS-deficient mice exhibit insulin resistance, including hyperglycemia, hyperinsulinemia, glucose intolerance, decreased insulin sensitivity, and increased hepatic glucose production. The administration of ectopic IRTKS can ameliorate the insulin resistance of IRTKS-deficient and diabetic mice. In parallel, the expression level of IRTKS was significantly decreased in diabetic mouse model. Furthermore, DNA hypermethylation of the IRTKS promoter was also observed in these subjects. We also show that IRTKS, as an adaptor of the insulin receptor (IR), modulates IR-IRS1-PI3K-AKT signaling via regulating the phosphorylation of IR. These findings add new insights into our understanding of insulin signaling and resistance.

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“…IRSp53 can enhance the activity of WAVE proteins, in both cases GTP-bound Rac1 is a key determinant of localization of these complexes [12,16]. The actin binding protein cortactin also binds to Arp3 and this helps to locate active Arp2/3 complexes to the sides of existing actin filaments leading to branched arrays of F-actin [17].…”

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confidence: 99%

The actin cytoskeleton in cancer cell motility

Olson

Sahai

2008

Clin Exp Metastasis

475

392

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Cancer cell metastasis is a multi-stage process involving invasion into surrounding tissue, intravasation, transit in the blood or lymph, extravasation, and growth at a new site. Many of these steps require cell motility, which is driven by cycles of actin polymerization, cell adhesion and acto-myosin contraction. These processes have been studied in cancer cells in vitro for many years, often with seemingly contradictory results. The challenge now is to understand how the multitude of in vitro observations relates to the movement of cancer cells in living tumour tissue. In this review we will concentrate on actin protrusion and acto-myosin contraction. We will begin by presenting some general principles summarizing the widely-accepted mechanisms for the co-ordinated regulation of actin polymerization and contraction. We will then discuss more recent studies that investigate how experimental manipulation of actin dynamics affects cancer cell invasion in complex environments and in vivo.

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IRSp53: crossing the road of membrane and actin dynamics in the formation of membrane protrusions

Cited by 243 publications

References 75 publications

Distinct VASP tetramers synergize in the processive elongation of individual actin filaments from clustered arrays

Distinct VASP tetramers synergize in the processive elongation of individual actin filaments from clustered arrays

Deficiency of IRTKS as an adaptor of insulin receptor leads to insulin resistance

The actin cytoskeleton in cancer cell motility

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