Wiskott-Aldrich syndrome (WAS) is an X chromosome-linked recessive disorder characterized by a crinical triad of eczema, thrombocytopenia and immunodeficiency. The gene responsible for this disorder was identified and shown to encode a multi-domain protein, Wiskott-Aldrich syndrome protein (WASP). WASP stimulates actin assembly through its C-terminus, but the physiological roles of the WASP N-terminus remain unknown.The principle investigator, I have identified calcium integrin binding protein (CIB) as a WASP N-terminus binding partner. The preliminary results suggest that WASP and CIB may participate in platelet aggregation and leukocyte migration by modulating integrins' affinities for their ligands. And also, I have isolated a cDNA encoding a novel WASP N-terminus-interacting protein (WIP-2). WJP-2 sequence suggests that WIP-2 is involved in chemotaxis. Based on these critical findings, to understand the roles of the WASP N-terminus in hematopoietic cells, the following specific aims are proposed.I. To elucidate the molecular mechanisms underlying the affinity modulation of integrin allb(33 for its ligand by WASP, CIB and PIP2 in platelets. II. To determine the molecular basis underlying bleeding in XLT patients. III. To determine the roles of WASP and CLB in chemotactic migration of leukocytes. IV. To determine the roles of a novel WASP N-terminus interacting protein (WIP-2) in Ieukocyte migration.Elucidating the roles of the WASP N-terminus in hematopoietic cells will provide important information about critical biological processes such as cell migration, and it should facilitate the development of potential therapeutic agent to treat XLT and WAS
| Tsuboi, Shigeru; Takada, Hidetoshi; Hara, Toshiro et al. (2009) FBP17 Mediates a Common Molecular Step in the Formation of Podosomes and Phagocytic Cups in Macrophages. J Biol Chem 284:8548-56 |
| Tsuboi, Shigeru; Meerloo, Jennifer (2007) Wiskott-Aldrich syndrome protein is a key regulator of the phagocytic cup formation in macrophages. J Biol Chem 282:34194-203 |
| Tsuboi, Shigeru (2007) Requirement for a complex of Wiskott-Aldrich syndrome protein (WASP) with WASP interacting protein in podosome formation in macrophages. J Immunol 178:2987-95 |
| Tsuboi, Shigeru; Nonoyama, Shigeaki; Ochs, Hans D (2006) Wiskott-Aldrich syndrome protein is involved in alphaIIb beta3-mediated cell adhesion. EMBO Rep 7:506-11 |
| Tsuboi, Shigeru (2006) A complex of Wiskott-Aldrich syndrome protein with mammalian verprolins plays an important role in monocyte chemotaxis. J Immunol 176:6576-85 |
