The Ras GTPase has been implicated in about 20% of all human cancers. The regulation of signal transduction through Ras is complex and is not fully understood. Multiple nucleotide exchange factors can activate Ras, and other factors called GTPase activating proteins (GAPs) can inactivate it. One such GAP, p120, can associate with another protein called p190, which is a GAP for the Rac/Rho GTPase family, and can thereby link these two signaling pathways. The activation of the Rac and Rho GTPases is required for transformation by Ras, and mediates changes in the actin cytoskeleton. The goals of this project are: (1) to understand the mechanisms that regulate the Ras exchange factor, p140 Ras-GRF; and (2) to determine the function of the GTP-binding domain in the p190 RhoGAP. GRF is expressed predominantly in neurons, and may be the key regulator of Ras activity in the brain. GRF can be controlled by phosphorylation of Ser residues in response to muscarinic receptor activation. The first specific aims include: (a) identification of the phosphorylated Ser residues; (b) identification of the protein kinase responsible for agonist-dependent GRF phosphorylation; (c) the function of the pleckstrin homology, coiled-coil, IQ and Dbl domains of GRF in regulating phosphorylation; and (d) the role of GRF in neuronal signal transduction. The GTP-binding domain of p190 RhoGAP is required for morphological and protein kinase responses of cells to p190 expression.
Specific aims i n this section include identification of: (e) the mechanism by which the GTP-binding domain exerts these effects and the role of the interaction of p190 with p120 RasGAP; and (f) factors that regulate p190 GTP binding and hydrolysis, using the isolated p190 GTP-binding domain as a substrate. Overall these studies should lead to significant new insights into signaling through the Ras pathway, and may lead to new therapeutic targets for certain types of cancer.
|Joberty, G; Petersen, C; Gao, L et al. (2000) The cell-polarity protein Par6 links Par3 and atypical protein kinase C to Cdc42. Nat Cell Biol 2:531-9|
|Mattingly, R R (1999) Phosphorylation of serine 916 of Ras-GRF1 contributes to the activation of exchange factor activity by muscarinic receptors. J Biol Chem 274:37379-84|
|Mattingly, R R; Saini, V; Macara, I G (1999) Activation of the Ras-GRF/CDC25Mm exchange factor by lysophosphatidic acid. Cell Signal 11:603-10|
|Tatsis, N; Lannigan, D A; Macara, I G (1998) The function of the p190 Rho GTPase-activating protein is controlled by its N-terminal GTP binding domain. J Biol Chem 273:34631-8|
|Wilson, D J; Fortner, K A; Lynch, D H et al. (1996) JNK, but not MAPK, activation is associated with Fas-mediated apoptosis in human T cells. Eur J Immunol 26:989-94|
|Brondyk, W H; McKiernan, C J; Fortner, K A et al. (1995) Interaction cloning of Rabin3, a novel protein that associates with the Ras-like GTPase Rab3A. Mol Cell Biol 15:1137-43|
|Mattingly, R R; Sorisky, A; Brann, M R et al. (1994) Muscarinic receptors transform NIH 3T3 cells through a Ras-dependent signalling pathway inhibited by the Ras-GTPase-activating protein SH3 domain. Mol Cell Biol 14:7943-52|
|Han, J W; McCormick, F; Macara, I G (1991) Regulation of Ras-GAP and the neurofibromatosis-1 gene product by eicosanoids. Science 252:576-9|
|Han, J W; Sadowski, H; Young, D A et al. (1990) Persistent induction of cyclooxygenase in p60v-src-transformed 3T3 fibroblasts. Proc Natl Acad Sci U S A 87:3373-7|
|Han, J W; Gaut, J; Burstein, E et al. (1990) The oncogenic protein p60v-src has competence activity but does not activate phosphatidylinositol turnover or protein kinase C in Balb/c 3T3 cells. Oncogene 5:467-74|
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