Recent advances in the biology of WASP and WIP

Division of Immunology, Department of Pediatrics, Childrens Hospital, Harvard Medical School, Karp 10 One Blackfan Circle, Boston, MA, 02115, USA.
Immunologic Research (Impact Factor: 3.1). 12/2008; 44(1-3):99-111. DOI: 10.1007/s12026-008-8086-1
Source: PubMed


WASP, the product of the gene mutated in Wiskott-Aldrich syndrome, is expressed only in hematopoietic cells and is the archetype of a family of proteins that include N-WASP and Scar/WAVE. WASP plays a critical role in T cell activation and actin reorganization. WASP has multiple protein-interacting domains. Through its N-terminal EVH1 domain WASP binds to its partner WASP interacting protein (WIP) and through its C-terminal end it interacts with and activates the Arp2/3 complex. In lymphocytes, most of WASP is sequestered with WIP and binding to WIP is essential for the stability of WASP. The central proline-rich region of WASP serves as docking site to several adaptor proteins. Through these multiple interactions WASP integrates many cellular signals to actin cytoskeleton remodeling. In this review, we have summarized recent developments in the biology of WASP and the role of WIP in regulating WASP function. We also discuss WASP-independent functions of WIP.

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    • "The VCA density in Nck SH3 clusters is always lower than 100% (Fig. 2A). This is because Nck SH3 domains have multiple binding partners besides N-WASP (Antoku et al., 2008; Kitamura et al., 1996; Quilliam et al., 1996; Ramesh and Geha, 2009; Schmidt and Dikic, 2005; Wunderlich et al., 1999; Zhao et al., 2000) and N-WASP can dissociate (Siton et al., 2011; Smith et al., 2013; Weisswange et al., 2009) from Nck SH3 domains after a new actin branch has been formed. Also at equilibrium only 38% of Nck molecules are predicted to be bound by N- WASP (based on estimates of Nck/N-WASP affinity and N-WASP abundance), and experimental and computational modeling data strongly suggest that the Nck:VCA stoichiometry in Nck comets is 2:1 (Ditlev et al., 2012). "
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    ABSTRACT: The Nck adaptor protein recruits cytosolic effectors such as N-WASP that induce localized actin polymerization. Experimental aggregation of Nck SH3 domains at the membrane induces actin comet tails, dynamic elongated filamentous actin structures similar to those that drive the movement of microbial pathogens such as Vaccinia virus. Here we show that experimental manipulation of the balance between unbranched/branched nucleation altered the morphology and dynamics of Nck-induced actin comets. Inhibition of linear formin-based nucleation with the small molecule inhibitor SMIFH2, or overexpression of the formin FH1 domain, resulted in formation of predominantly circular-shaped actin structures with low mobility (actin blobs). These results indicate that formin-based linear actin polymerization is critical for the formation and maintenance of Nck-dependent actin comet tails. Consistent with this, aggregation of an exclusively branched nucleation promoting factor (the VCA domain of N-WASP), with the density and turnover similar to that of N-WASP in Nck comets, did not reconstitute dynamic elongated actin comets. Furthermore, enhancement of branched Arp2/3-mediated nucleation by N-WASP overexpression caused loss of the typical actin comet tail shape induced by Nck aggregation. Thus the ratio of linear to dendritic nucleation activity may serve to distinguish the properties of actin structures induced by various viral and bacterial pathogens.
    Preview · Article · Nov 2015 · Molecular biology of the cell
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    • "Similar numbers of genes were significantly up- or downregulated (269 up-regulated, 225 downregulated; Figure 5(a), Table S4). Many of the upregulated transcripts are involved in regulating neurotransmission (otoferlin, Otof [41]: Wiskott-Aldrich syndrome protein interacting protein family 1, Wipf1 [42]; neurotrophin receptor tyrosine kinase 3, Ntrk3 [43]; calcium/calmodulin kinase 1D, CamK1d [44]) and differentiation YLP motif containing 1 (Ylpm1 [45]). CR in the WT animals, however, caused profound suppression of multiple energy-modulatory factors including insulin-like growth factor 1 (Igf1), phospholipid transfer protein (Pltp), and neuronal ceroid lipofuscinosis 6 (Cln6), which were significantly downregulated following CR. "
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    ABSTRACT: The hypothalamus is an essential relay in the neural circuitry underlying energy metabolism that needs to continually adapt to changes in the energetic environment. The neuroendocrine control of food intake and energy expenditure is associated with, and likely dependent upon, hypothalamic plasticity. Severe disturbances in energy metabolism, such as those that occur in obesity, are therefore likely to be associated with disruption of hypothalamic transcriptomic plasticity. In this paper, we investigated the effects of two well-characterized antiaging interventions, caloric restriction and voluntary wheel running, in two distinct physiological paradigms, that is, diabetic ( db/db ) and nondiabetic wild-type ( C57/Bl/6 ) animals to investigate the contextual sensitivity of hypothalamic transcriptomic responses. We found that, both quantitatively and qualitatively, caloric restriction and physical exercise were associated with distinct transcriptional signatures that differed significantly between diabetic and non-diabetic mice. This suggests that challenges to metabolic homeostasis regulate distinct hypothalamic gene sets in diabetic and non-diabetic animals. A greater understanding of how genetic background contributes to hypothalamic response mechanisms could pave the way for the development of more nuanced therapeutics for the treatment of metabolic disorders that occur in diverse physiological backgrounds.
    Full-text · Article · Aug 2012 · International Journal of Endocrinology
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    • "Binding to WIP not only inhibits WASp but also is necessary for its stability. Furthermore, WIP is also a chaperone of WASp, regulating its activation and is responsible for the localization of WASp at actin rearrangement site followed by T cell activation (86-88). WIP was reported to be essential for IL-2 signalling and responsiveness in T cells (89). "
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    ABSTRACT: T cell activation and function require physical contact with antigen presenting cells at a specialized junctional structure known as the immunological synapse. Once formed, the immunological synapse leads to sustained T cell receptor-mediated signalling and stabilized adhesion. High resolution microscopy indeed had a great impact in understanding the function and dynamic structure of immunological synapse. Trends of recent research are now moving towards understanding the mechanical part of immune system, expanding our knowledge in mechanosensitivity, force generation, and biophysics of cell-cell interaction. Actin cytoskeleton plays inevitable role in adaptive immune system, allowing it to bear dynamic and precise characteristics at the same time. The regulation of mechanical engine seems very complicated and overlapping, but it enables cells to be very sensitive to external signals such as surface rigidity. In this review, we focus on actin regulators and how immune cells regulate dynamic actin rearrangement process to drive the formation of immunological synapse.
    Full-text · Article · Jun 2012 · Immune Network
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