WIP is a chaperone for Wiskott–Aldrich syndrome protein (WASP)

Fuente, Miguel A. de la; Sasahara, Yoji; Calamito, Marco; Antón, Inés M.; Elkhal, Abdallah; Gallego, M. Dolores; Suresh, K.; Siminovitch, Katherine A.; Ochs, Hans D.; Anderson, Kenneth C.; Rosen, Fred S.; Geha, Raif S.; Ramesh, Narayanaswamy

doi:10.1073/pnas.0610275104

Cited by 149 publications

(188 citation statements)

References 41 publications

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“…Mutations in the WH1 domain abrogate WIP binding, and levels of WASp are markedly diminished as a result of degradation. Similarly, WIP-/-mice have very low levels of WASp (8,33). Treatment of such cells with calpain inhibitors and/or proteasome inhibitors results in partial restoration of protein levels, suggesting that calpain and the ubiquitin-proteasome play an important role in turnover.…”

Section: Discussionmentioning

confidence: 99%

“…As patients with constitutively active mutations appear to express relatively normal levels of WASp, phosphorylation and degradation may be intimately linked. The levels of WASp within a cell have been shown to be regulated by calpain and the ubiquitinproteasome (8,10). In normal cells, the majority of WASp is complexed with its chaperone WIP.…”

Section: Discussionmentioning

confidence: 99%

“…Biochemical studies indicate that non-activated WASp assumes an autoinhibitory conformation in which the VCA domain interacts with the hydrophobic core of the GTPase binding domain (GBD) (7). The N-terminal WH1 domain also binds the chaperone, WASp-interacting protein (WIP) (8,9), in the absence of which WASp is unstable (10). Activation of WASp by cooperative binding of PIP 2 and GTP-bound Cdc42 is thought to structurally disrupt the autoinhibitory confirmation allowing binding of the Arp2/3 complex to the C terminus (11)(12)(13).…”

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confidence: 99%

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Phosphorylation of WASp is a key regulator of activity and stability in vivo

Blundell

Bouma

Metelo

et al. 2009

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

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The Wiskott-Aldrich syndrome protein (WASp) is a key cytoskeletal regulator in hematopoietic cells. Covalent modification of a conserved tyrosine by phosphorylation has emerged as an important potential determinant of activity, although the physiological significance remains uncertain. In a murine knockin model, mutation resulting in inability to phosphorylate Y293 (Y293F) mimicked many features of complete WASp-deficiency. Although a phosphomimicking mutant Y293E conferred enhanced actin-polymerization, the cellular phenotype was similar due to functional dysregulation. Furthermore, steady-state levels of Y293E-WASp were markedly reduced compared to wild-type WASp and Y293F-WASp, although partially recoverable by treatment of cells with proteasome inhibitors. Consequently, tyrosine phosphorylation plays a critical role in normal activation of WASp in vivo, and is indispensible for multiple tasks including proliferation, phagocytosis, chemotaxis, and assembly of adhesion structures. Furthermore, it may target WASp for proteasome-mediated degradation, thereby providing a default mechanism for self-limiting stimulation of the Arp2/3 complex. actin polymerization ͉ immune deficiency ͉ Wiskott-Aldrich syndrome

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Phosphorylation of WASp is a key regulator of activity and stability in vivo

Blundell

Bouma

Metelo

et al. 2009

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

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“…Upon DNA damage, there is enhanced cytoplasmic actin polymerization, which sequesters monomeric actin into F-actin. This effectively decreases the binding of G-actin to the WH2 domains, thereby exposing the NLS; this then results in importin binding, JMY nuclear accumulation and p53-dependent gene expression (Zuchero et al, 2012 Fuente et al, 2007;Ramesh et al, 1997) and is required to stabilize WASP. Direct binding to the GTPase-binding domain (GBD) of WASP by the GTP-bound form of Cdc42, a member of the Rho GTPase family, relieves an autoinhibitory fold (Kim et al, 2000).…”

Section: Jmymentioning

confidence: 99%

Cellular functions of WASP family proteins at a glance

Alekhina

Burstein

Billadeau

2017

Journal of Cell Science

165

172

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Proteins of the Wiskott–Aldrich syndrome protein (WASP) family function as nucleation-promoting factors for the ubiquitously expressed Arp2/3 complex, which drives the generation of branched actin filaments. Arp2/3-generated actin regulates diverse cellular processes, including the formation of lamellipodia and filopodia, endocytosis and/or phagocytosis at the plasma membrane, and the generation of cargo-laden vesicles from organelles including the Golgi, endoplasmic reticulum (ER) and the endo-lysosomal network. Recent studies have also identified roles for WASP family members in promoting actin dynamics at the centrosome, influencing nuclear shape and membrane remodeling events leading to the generation of autophagosomes. Interestingly, several WASP family members have also been observed in the nucleus where they directly influence gene expression by serving as molecular platforms for the assembly of epigenetic and transcriptional machinery. In this Cell Science at a Glance article and accompanying poster, we provide an update on the subcellular roles of WHAMM, JMY and WASH (also known as WASHC1), as well as their mechanisms of regulation and emerging functions within the cell.

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“…For example, WIP is required for targeting WASP to the immune synapse after T-cell receptor ligation (6,17). WIP expression is required for the functional expression of WASP in hematopoietic cells (37,38), and in WIP-deficient mice, T cells fail to proliferate or polarize in response to T-cell-receptor ligation and form smaller T cellantigen-presenting cells conjugate interfaces (26). WIP also binds directly to F-actin and inhibits Ccd42-mediated actin polymerization; it synergizes with N-WASP to induce filopodia when overexpressed in fibroblasts (39).…”

Section: The Wiskott-aldrich Syndrome (Was)mentioning

confidence: 99%

Wiskott-Aldrich Syndrome Protein Is a Key Regulator of the Phagocytic Cup Formation in Macrophages

Tsuboi

Meerloo

2007

Journal of Biological Chemistry

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Phagocytosis is a vital first-line host defense mechanism against infection involving the ingestion and digestion of foreign materials such as bacteria by specialized cells, phagocytes. For phagocytes to ingest the foreign materials, they form an actin-based membrane structure called phagocytic cup at the plasma membranes. Formation of the phagocytic cup is impaired in phagocytes from patients with a genetic immunodeficiency disorder, Wiskott-Aldrich syndrome (WAS). The gene defective in WAS encodes Wiskott-Aldrich syndrome protein (WASP). Mutation or deletion of WASP causes impaired formation of the phagocytic cup, suggesting that WASP plays an important role in the phagocytic cup formation. However, the molecular details of its formation remain unknown. We have shown that the WASP C-terminal activity is critical for the phagocytic cup formation in macrophages. We demonstrated that WASP is phosphorylated on tyrosine 291 in macrophages, and the WASP phosphorylation is important for the phagocytic cup formation. In addition, we showed that WASP and WASPinteracting protein (WIP) form a complex at the phagocytic cup and that the WASP⅐WIP complex plays a critical role in the phagocytic cup formation. Our results indicate that the phosphorylation of WASP and the complex formation of WASP with WIP are the essential molecular steps for the efficient formation of the phagocytic cup in macrophages, suggesting a possible disease mechanism underlying phagocytic defects and recurrent infections in WAS patients. The Wiskott-Aldrich syndrome (WAS)2 is an X chromosome-linked immunodeficiency disorder. Patients with WAS suffer from severe bleeding, eczema, recurrent infections, autoimmune diseases, and an increased risk of lymphoreticular malignancy (1-3). The causative gene underlying WAS encodes Wikott-Aldrich syndrome protein (WASP) (4). WASP is a 62-kDa cytosolic protein comprising distinct domains that interact with other cellular factors to regulate, mediate, and target the many functions of WASP (Fig. 3A) (5, 6). WASP is expressed predominantly in hematopoietic cells and functions in the assembly of the actin cytoskeleton (7, 8), signal transduction (9 -12), apoptosis (13,14), and the regulation of gene expression (15,16). Furthermore, WASP translocates to lipid rafts after T-cell receptor ligation, localizing to immune synapses, the junctions between T cells, and antigen-presenting cells (17,18), and recent investigations of T-cell profiles from WASP-deficient mice have revealed a critical role for WASP in regulatory T-cell function (19 -21).The WASP C-terminal region (residues 178 -502) regulates the organization of the actin cytoskeleton. Phosphatidylinositol 4,5-bisphosphate binds to the Basic Region, whereas Cdc42 binds the GTPase binding domain. Binding of these cellular factors activates the WASP C-terminal VCA (verprolin/cofilin/ acidic) domain, which in turn activates the actin-related protein complex (Arp2/3 complex), stimulating actin polymerization through the formation of F-actin branch junctions (8,22,23). ...

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WIP is a chaperone for Wiskott–Aldrich syndrome protein (WASP)

Cited by 149 publications

References 41 publications

Phosphorylation of WASp is a key regulator of activity and stability in vivo

Phosphorylation of WASp is a key regulator of activity and stability in vivo

Cellular functions of WASP family proteins at a glance

Wiskott-Aldrich Syndrome Protein Is a Key Regulator of the Phagocytic Cup Formation in Macrophages

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