The high grade human brain tumors known as glioblastoma multiforme are characterized by an increase in cell proliferation, resistance to apoptosis, and enhanced vascularity. The search for the molecular mechanisms has strongly implicated receptor tyrosine kinases pathways. The objective of this project is to study the downstream pathways for these tyrosine kinase receptors in hopes to improve our understanding of glial tumorigenesis. A better understanding of these pathways will hopefully lead us to improved therapeutics directed at malignant brain tumors. Previous work in the lab of Dr. Albert Wong has shown that expression of JNK2a2 promotes several tumorigenic phenotypes including cell growth and tumorigenicity. His lab also cloned the Gab1 docking protein, which is an essential component in receptor tyrosine kinases pathways that promotes cell growth, survival, and vascularity. There is strong evidence that Gab1 acts as an important accessory for JNK and ERK function. ERK binds to the Met binding domain (MBD) present in Gab1 and this can result in Gab1 phosphorylation by ERK. Gab1 is essential for ERK function as ERK lacks a nuclear localization signal (NLS) and instead relies on its association with Gab1, which does have a NLS, for importation into the nucleus. It has been found that Gab1 is essential for the activation of JNK following stimulation by H2O2 and that JNK also associates with Gab1. For these reasons, we believe that Gab1 is an essential component for JNK2a2 function in cells. The goal of this project is to determine the role of the Gab1: JNK2a2 complex in mediating JNK2a2 signaling and its role in glial tumorigenesis. In the first specific aim, we will first establish the site on Gab1 that interacts with JNK2a2. Using this information, in specific Aim #2, we will determine where the Gab1: JNK2a2 complexes directly interact. Should we find that the active Gab1: JNK2a2 complex localizes to the nucleus, we will confirm that this is due to the nuclear transport by Gab1.
In specific aim #3, we will determine the role of the Gab1:JNK2a2 complex in mediating AKT and PI 3-kinase activation. Using dominant negative mutants of Gab1 that interfere with the binding to JNK2a2, we will show that this has an effect on interfering with several aspects of the glial tumor phenotypes. Ultimately, this information may be useful for designing therapeutics for the downregulation of signaling pathways in brain tumors. In plain language, we are studying the molecular biology of malignant brain tumors in hope to find better treatment options for this tumor.
|Li, Gordon; Mitra, Siddhartha; Karamchandani, Jason et al. (2010) Pineal parenchymal tumor of intermediate differentiation: clinicopathological report and analysis of epidermal growth factor receptor variant III expression. Neurosurgery 66:963-8; discussion 968|