A central question to be addressed in cell regulation is the biochemical mechanism by which many different kinds of signaling proteins and enzymes work in concert to mediate cellular responses to a specific extracellular stimulus. We are just beginning to appreciate that scaffold or adapter proteins may play important roles in signal relay from the plasma membrane to intracellular targets by aggregating a variety of proteins into specific signaling pathways or networks. We and others have recently identified a novel human scaffold protein, Gab2, that is closely related to Gab I (Grb2-associated binder 1) and Drosophila Dos (daughter of sevenless). Both Gabi and Gab2 contain a PH domain and mutliple potential tyrosine phosphorylation sites for SH2 proteins as well as proline-rich motifs for SH3 binding. Interestingly, we have found that Gabi and Gab2 exhibit reciprocal functions in coupling cytoplasmic-nuclear signaling, and that Gab2 acts to suppress the activity of the transcription factor Elk-i induced by oncogenic RasV 12 or epidermal growth factor, without down-regulating extracellular signal-regulated kinase (Erk) activity. We hypothesize that Gab2 acts to aggregate a unique set of enzymes and their specific substrates for signal relay, which represents a novel and unexplored pathway in intracellular signaling. The goal of this proposal is to dissect this pathway for the negative effect of Gab2 in signal transduction. This will be accomplished by: 1). identification of the structural domain in Gab2 involved in the negative regulatory role; 2). isolation and functional analysis of proteins that interact with Gab2 through the """"""""negative effect domain""""""""; 3). elucidation of the physiological consequence of the Gab2 interaction with its partners; and 4). determination of the biological function of Gab2 in vivo by generating a Gab2-deficient mouse model. This work will enable us to understand better the mechanism whereby the specificity of intracellular signaling is achieved through organization of multimolecular complexes (signalsomes) by scaffold proteins, such as Gab2, and will also aid in designing efficient pharmaceutical intervention of certain cellular disorders associated with heart failure, diabetes and malignant diseases.
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