WIP regulates N-WASP-mediated actin polymerization and filopodium formation

Martı́nez-Quiles, Narcisa; Rohatgi, Rajat; Antón, Inés M.; Medina, Miguel; Saville, Stephen P.; Miki, Hiroaki; Yamaguchi, Hideki; Takenawa, Tadaomi; Hartwig, John H.; Geha, Raif S.; Ramesh, Narayanaswamy

doi:10.1038/35074551

Cited by 254 publications

(254 citation statements)

References 36 publications

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“…One possible function is that full-length MIM has an F-actin binding activity (data not shown), which may facilitate cortactin-mediated actin polymerization. Consistent with this view, WIP, which is able to activate cortactin by nearly twofolds (Kinley et al, 2003), also shows an F-actin binding activity (Martinez-Quiles et al, 2001).…”

Section: Discussionsupporting

confidence: 68%

Differential regulation of cortactin and N-WASP-mediated actin polymerization by missing in metastasis (MIM) protein

et al. 2005

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Section: Discussionsupporting

confidence: 68%

Differential regulation of cortactin and N-WASP-mediated actin polymerization by missing in metastasis (MIM) protein

et al. 2005

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“…1C), together with published affinity values for various WH2 (6,15,16) and T␤ (21,22) domains, consistently show that WH2 binds actin with Ϸ10-fold higher affinity than T␤. Owing to the presence of the C-terminal ␣-helix, T␤ has a larger actin-binding interface than WH2 (Fig.…”

Section: Resultsmentioning

confidence: 94%

“…1A), which constitutes the smallest fragment necessary for Arp2͞3 activation (4). WH2 is also present in members of the WASP-interacting protein (WIP) family, which form complexes with WASP͞N-WASP and modulate their functions in vivo (5,6). Members of this family include WIP, CR16, and WIRE (or WICH) in mammals and verprolin in yeast.…”

mentioning

confidence: 99%

Actin-bound structures of Wiskott–Aldrich syndrome protein (WASP)-homology domain 2 and the implications for filament assembly

Chéreau

Kerff

Graceffa

et al. 2005

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

236

375

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Wiskott-Aldrich syndrome protein (WASP)-homology domain 2 (WH2) is a small and widespread actin-binding motif. In the WASP family, WH2 plays a role in filament nucleation by Arp2͞3 complex. Here we describe the crystal structures of complexes of actin with the WH2 domains of WASP, WASP-family verprolin homologous protein, and WASP-interacting protein. Despite low sequence identity, WH2 shares structural similarity with the N-terminal portion of the actin monomer-sequestering thymosin ␤ domain (T␤). We show that both domains inhibit nucleotide exchange by targeting the cleft between actin subdomains 1 and 3, a common binding site for many unrelated actin-binding proteins. Importantly, WH2 is significantly shorter than T␤ but binds actin with Ϸ10-fold higher affinity. WH2 lacks a C-terminal extension that in T␤4 becomes involved in monomer sequestration by interfering with intersubunit contacts in F-actin. Owing to their shorter length, WH2 domains connected in tandem by short linkers can coexist with intersubunit contacts in F-actin and are proposed to function in filament nucleation by lining up actin subunits along a filament strand. The WH2-central region of WASP-family proteins is proposed to function in an analogous way by forming a special class of tandem repeats whose function is to line up actin and Arp2 during Arp2͞3 nucleation. The structures also suggest a mechanism for how profilin-binding Pro-rich sequences positioned N-terminal to WH2 could feed actin monomers directly to WH2, thereby playing a role in filament elongation.x-ray crystallography ͉ isothermal titration calorimetry ͉ nucleotide exchange T he actin cytoskeleton plays an essential role in many cellular functions, including intracellular transport and the control of cell shape and polarity (1). In the cell, a vast number of actin-binding proteins (ABPs) direct the location, rate, and timing for actin assembly into different structures, such as filopodia, lamellipodia, stress fibers, and focal adhesions. ABPs are commonly multidomain proteins, containing signaling domains and structurally conserved actin-binding motifs. One of the most abundant actin-binding motifs is Wiskott-Aldrich syndrome protein (WASP)-homology domain 2 (WH2) (2). The hematopoietic-specific protein, WASP, and its ubiquitously expressed ortholog N-WASP form part of a family that also includes the three WASP-family verprolin homologous protein (WAVE͞SCAR) isoforms: WAVE1, WAVE2, and WAVE3 (1, 3). Members of this family activate Arp2͞3-dependent actin nucleation and branching in response to signals mediated by Rho-family GTPases. Although the domain structure of these proteins varies, reflecting different modes of regulation, they all share a common C-terminal WH2 central-acidic region (CA region) (Fig. 1A), which constitutes the smallest fragment necessary for Arp2͞3 activation (4). WH2 is also present in members of the WASP-interacting protein (WIP) family, which form complexes with WASP͞N-WASP and modulate their functions in vivo (5, 6). Members of this family include ...

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“…A complex of WASP with WIP functions in important cellular processes in T cells, fibroblasts or monocytes (15,16,31,32). It has been shown that WASP localizes at podosomes and plays a critical role in podosome formation (28,33).…”

Section: Wasp Binds Wip To Form a Complex At Podosomesmentioning

confidence: 99%

Requirement for a Complex of Wiskott-Aldrich Syndrome Protein (WASP) with WASP Interacting Protein in Podosome Formation in Macrophages

Tsuboi

2007

The Journal of Immunology

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Chemotactic migration of macrophages is critical for the recruitment of leukocytes to inflamed tissues. Macrophages use a specialized adhesive structure called a podosome to migrate. Podosome formation requires the Wiskott-Aldrich syndrome protein (WASP), which is a product of the gene defective in an X-linked inherited immunodeficiency disorder, the Wiskott-Aldrich syndrome. Macrophages from WASP-deficient Wiskott-Aldrich syndrome patients lack podosomes, resulting in defective chemotactic migration. However, the molecular basis for podosome formation is not fully understood. I have shown that the WASP interacting protein (WIP), a binding partner of WASP, plays an important role in podosome formation in macrophages. I showed that WASP bound WIP to form a complex at podosomes and that the knockdown of WIP impairs podosome formation. When WASP binding to WIP was blocked, podosome formation was also impaired. When WASP expression was reduced by small interfering RNA transfection, the amount of the complex of WASP with WIP decreased, resulting in reduced podosome formation. Podosomes were restored by reconstitution of the WASP-WIP complex in WASP knockdown cells. These results indicate that the WASP-WIP complex is required for podosome formation in macrophages. When podosome formation was reduced by blocking WASP binding to WIP, transendothelial migration of macrophages, the most crucial process in macrophage trafficking, was impaired. These results suggest that a complex of WASP with WIP plays a critical role in podosome formation, thereby mediating efficient transendothelial migration of macrophages.

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WIP regulates N-WASP-mediated actin polymerization and filopodium formation

Cited by 254 publications

References 36 publications

Differential regulation of cortactin and N-WASP-mediated actin polymerization by missing in metastasis (MIM) protein

Differential regulation of cortactin and N-WASP-mediated actin polymerization by missing in metastasis (MIM) protein

Actin-bound structures of Wiskott–Aldrich syndrome protein (WASP)-homology domain 2 and the implications for filament assembly

Requirement for a Complex of Wiskott-Aldrich Syndrome Protein (WASP) with WASP Interacting Protein in Podosome Formation in Macrophages

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