Research
Our long-term objective is to understand homeostatic control of cytokine-mediated cell signaling in health and disease. Currently our major focus is to define (i) the role and regulation of Stat3 signaling in the survival of glioblastoma cells, (ii) the cellular and molecular mechanisms that negatively regulate IL-4-mediated signal transduction and subsequent gene expression in allergic inflammation, and (iii) signaling mechanisms underlying the growth and survival of mast cells.
A. Cytokine Signaling in Glioblastoma Cells
Glioblastoma multiforme (GBM) is the most common and malignant form of primary brain tumors, with an average survival of less than one year. The latent transcription factor Stat3, when activated by IL-6-family cytokines and other growth factors, induces the expression of genes that are responsible for suppression of apoptosis in a variety of human cancer cells. We found that Stat3 is persistently activated by the autocrine action of IL-6 in GBM tumor tissues and GBM cell lines. Inhibition of Stat3 activation induces apoptosis in these cells. We have undertaken biochemical and molecular genetic approaches in both tissue culture system and animal models to investigate the molecular bases of Stat3-mediated survival of GBM cells. In addition, we have addressed the role of IL-13Ra2, a high-affinity non-signaling transmembrane IL-13-binding protein, in the regulation of Jak-Stat signaling in GBM cells.
B. Cytokine Signaling in Allergic Inflammation
Negative Regulation of IL-4 Signaling
IL-4, a pleiotropic cytokine secreted by activated T lymphocytes, basophils and mast cells, plays a key role in the pathogenesis of a variety of inflammatory disorders, including allergic asthma and other allergic diseases. Major biological actions of IL-4 in the inflammatory cells are mediated through the activation of the Jak-Stat pathway. Signal transduction through this pathway can be negatively controlled at multiple levels by a number of molecules and by different means. We chose to focus on the roles of PTPs and SOCS-family proteins in the negative regulation of IL-4-dependent Jak-Stat signaling. Our recent work suggested that PTP activity is a major and primary negative regulator of the cytokine-activated Jak-Stat signaling pathway, and importantly, more than one PTP activity is involved in this process. We have identified Shp-1 as negative regulator of IL-4-mediated cell signaling. Identification of Shp-1 substrate(s), additional PTPs and their substrates in these signaling pathways is under active investigation. To understand the SOCS-mediated negative feedback mechanisms, we have begun to characterize the induction profile of SOCS genes in cytokine-stimulated cells and to define the structural basis of SOCS-mediated regulation of the Jak-Stat signaling pathways.
Signaling Mast Cell Growth and Survival
Mast cells are critical effectors in innate immune responses and play key roles in the pathogenesis of multiple inflammatory disorders including asthma. Stem cell factor (SCF) signaling through c-Kit is essential for proliferation and survival of human mast cells. However, the precise molecular mechanisms underlying c-Kit-mediated mast cell survival remain unclear. The long-term goal of this project is to (i) identify and characterize intracellular signaling transduction pathways that lead to the expression and activation of pro-survival proteins in mast cells, and (ii) target the identified pathways in a mouse asthma model to induce the spontaneous apoptosis of airway mast cells.