Recent advances in the biology of WASP and WIP
ABSTRACT 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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- "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 : Wiskott-Aldrich syndrome protein interacting protein family 1, Wipf1 ; neurotrophin receptor tyrosine kinase 3, Ntrk3 ; calcium/calmodulin kinase 1D, CamK1d ) and differentiation YLP motif containing 1 (Ylpm1 ). 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. "
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.International Journal of Endocrinology 08/2012; 2012:732975. DOI:10.1155/2012/732975 · 1.52 Impact Factor
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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). "
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.Immune Network 06/2012; 12(3):71-83. DOI:10.4110/in.2012.12.3.71
- "Wiskott-Aldrich syndrome protein interacting protein (WIP) is another important regulator of the actin cytoskeleton that inhibits Cdc42-mediated activation of WASP. Most of WASP in lymphocytes appear to be sequestered with WIP, and binding to WIP is essential for the stability of WASP (Ramesh and Geha, 2009). More efficient generation of actin filaments was detected in WIP-deficient BMMCs activated by FcεRI aggregation (Kettner et al., 2004). "
Article: Cytoskeleton in Mast Cell Signaling[Show abstract] [Hide abstract]
ABSTRACT: Mast cell activation mediated by the high affinity receptor for IgE (FcεRI) is a key event in allergic response and inflammation. Other receptors on mast cells, as c-Kit for stem cell factor and G protein-coupled receptors (GPCRs) synergistically enhance the FcεRI-mediated release of inflammatory mediators. Activation of various signaling pathways in mast cells results in changes in cell morphology, adhesion to substrate, exocytosis, and migration. Reorganization of cytoskeleton is pivotal in all these processes. Cytoskeletal proteins also play an important role in initial stages of FcεRI and other surface receptors induced triggering. Highly dynamic microtubules formed by αβ-tubulin dimers as well as microfilaments build up from polymerized actin are affected in activated cells by kinases/phosphatases, Rho GTPases and changes in concentration of cytosolic Ca(2+). Also important are nucleation proteins; the γ-tubulin complexes in case of microtubules or Arp 2/3 complex with its nucleation promoting factors and formins in case of microfilaments. The dynamic nature of microtubules and microfilaments in activated cells depends on many associated/regulatory proteins. Changes in rigidity of activated mast cells reflect changes in intermediate filaments build up from vimentin. This review offers a critical appraisal of current knowledge on the role of cytoskeleton in mast cells signaling.Frontiers in Immunology 05/2012; 3:130. DOI:10.3389/fimmu.2012.00130