THE INOSITOL 5-PHOSPHATASE SHIP AND MAST CELL FUNCTION

肥大细胞的激活可以在多种免疫和非免疫刺激下发生。然而，肥大细胞的功能也受到抑制受体的调节，抑制受体通过相关的酪氨酸磷酸酶SHP-1和/或SHP-2以及肌醇5-磷酸酶SHIP转导细胞内信号。最近的研究表明SHIP在调节淋巴细胞和髓细胞的抗原受体信号传导中起重要作用。此外，SHIP在缺乏抗原的情况下对防止肥大细胞活化至关重要。目前尚不清楚SHIP如何被招募到介导这种调节功能的位点。在初步研究中，我们在肥大细胞中鉴定了四种新的SHIP结合膜糖蛋白。我们假设这些糖蛋白中的一种或多种可能在肥大细胞功能调节中起抑制分子的作用。此外，基于最近在B细胞中的研究，我们假设这些和先前定义的抑制分子通过与SHIP及其效应物p62dok的关联来调节肥大细胞的功能。本提案的具体目的是：1)鉴定在肥大细胞中介导SHIP激活的新型抑制分子；2)确定SHIP和p62dok在调节肥大细胞功能中的作用。

Mast cell activation can occur in response to a variety of immunologic and non-immunologic stimuli. However, mast cell function is also subject to regulation by inhibitory receptors that transduce intracellular signals via associated tyrosine phosphatases, SHP-1 and/or SHP-2, and the inositol 5-phosphatase SHIP. Recent studies have demonstrated an important role for SHIP in regulating antigen receptor signaling in lymphoid and myeloid cells. In addition, SHIP is critical for preventing mast cell activation in the absence of antigen. It is presently unknown how SHIP is recruited into sites where it mediates this regulatory function. In preliminary studies, we have identified four novel SHIP- binding membrane glycoproteins in mast cells. We hypothesize that one or more of these glycoproteins may function as inhibitory molecules in the regulation of mast cell function. Furthermore, based on recent studies in B cells, we hypothesize that these and previously defined inhibitory molecules regulate mast cell function via association with SHIP and its effector p62dok. The specific aims of this proposal are to 1) identify novel inhibitory molecules that mediate SHIP activation in mast cells, and 2) define the role of SHIP and p62dok in regulating mast cell function.