Disease relevance of Wasl

• Our results indicate that WIP and N-WASP may act as a functional unit in filopodium formation, which is consistent with their role in actin-tail formation in cells infected with vaccinia virus or Shigella [1].
• In addition, enteropathogenic Escherichia coli were incapable of inducing the formation of actin pedestals in N-WASP-defective cells [2].

High impact information on Wasl

• EphB receptors regulate dendritic spine development via intersectin, Cdc42 and N-WASP [3].
• WIP regulates N-WASP-mediated actin polymerization and filopodium formation [1].
• Induction of filopodia is dependent on activation of the small GTPase Cdc42 and on neural Wiskott-Aldrich-syndrome protein (N-WASP) [1].
• Microinjection of WIP into NIH 3T3 fibroblasts induces filopodia; this is inhibited by microinjection of anti-N-WASP antibody [1].
• Microinjection of anti-WIP antibody inhibits induction of filopodia by bradykinin, by an active Cdc42 mutant (Cdc42(V12)) and by N-WASP [1].

Biological context of Wasl

• We suggest that N-WASP and the Arp2/3 complex trigger actin polymerization during a late step in clathrin-mediated endocytosis, and propel clathrin-coated pits or vesicles from the plasma membrane into the cytoplasm [4].
• Together, these results suggest a novel regulatory mechanism of N-WASP by tyrosine phosphorylation and subcellular localization and its potential role in the regulation of cell migration [5].
• These results imply a crucial and non-redundant role for N-WASP in murine embryogenesis and in the actin-based motility of certain pathogens but not in the general formation of actin-containing structures [6].
• Whereas N-WASP-deficient embryos survive beyond gastrulation and initiate organogenesis, they have marked developmental delay and die before embryonic day 12 [6].
• Twinfilin replaces capping protein and promotes motility of N-WASP functionalized beads in a biomimetic motility assay, indicating that the capping activity supports twinfilin's function in motility [7].

Anatomical context of Wasl

• Neural Wiskott Aldrich Syndrome Protein (N-WASP) and the Arp2/3 complex are recruited to sites of clathrin-mediated endocytosis in cultured fibroblasts [4].
• N-WASP is a member of the WASP family of proteins that regulate actin cytoskeleton remodeling [5].
• We show that the endocytic protein, dynamin, competes for binding to the SH3 domains with the neural Wiskott-Aldrich Syndrome protein, an actin filament nucleation protein that is a substrate for activated Cdc42 [8].
• To elucidate the role of N-WASP at the cellular level, we immortalized embryonic fibroblasts and selected various N-WASP-defective cell lines [2].
• On the other hand, under culture conditions that inhibit neurite extension, but favor proliferation, the phosphorylated N-WASP is degraded rapidly [9].

Associations of Wasl with chemical compounds

• In contrast, wiskostatin, a chemical inhibitor of N-WASP, potently suppressed dorsal ruffle formation in a dose-dependent manner [10].

Physical interactions of Wasl

• Here we show that WASP-interacting protein (WIP) interacts directly with N-WASP and actin [1].
• We first isolated N-WASP as one of the proteins bound to Ash/Grb2 SH3 domain [11].
• In addition, this actin-clustering could not be suppressed by the coexpression of the Arp2/3 complex-sequestering fragment (CA-region) derived from N-WASP, which clearly inhibits Rac-induced membrane ruffling [12].

Regulatory relationships of Wasl

• N-WASP activates Arp2/3 complex-dependent actin polymerization through the VCA region, leading to filopodium formation [11].

Other interactions of Wasl

• Moreover, exogenous expression of wild-type N-WASP or WAVE2 promoted lamellipodial formation and migration [13].
• Moreover, overexpression of N-terminal fragments of Scar2 (but not N-WASP or Scar1 or Scar3) interfere with NIH 3T3 Golgi polarization but not with cell migration [14].
• Focal adhesion kinase regulation of N-WASP subcellular localization and function [5].
• Phosphorylation of Tyr(256) of N-WASP could reduce its interaction with nuclear importin NPI-1, which might be responsible for its decreased nuclear localization [5].

Analytical, diagnostic and therapeutic context of Wasl

• We employed Cre/loxP-mediated gene targeting to disrupt the ubiquitously expressed N-WASP in the mouse germline, which led to embryonic lethality [2].
• A partial reversal of the T-cell signaling defect could also be achieved following transplantation of WASP-deficient HSCs expressing the WASP-homologous protein N-WASP [15].

References