G-Protein Signaling Through Tubby Proteins
The tubby gene product is expressed in the brain and has been implicated by mouse genetics in obesity and other disorders such as blindness. Structural analysis predicted that this gene acts as a transcription factor, binding to DNA to regulate gene expression. More recently, it was reported that tubby binds to phosphoinositides in the plasma membrane, helping to localize this factor in the membrane region in the absence of pathway activation. Tubby also interacts with Galpha-q g-protein subunits, localizing tubby to regions of g-protein activation. Activation of phosphipase C activity and hydrolysis of membrane phosphoinositides leads to release of tubby from the plasma membrane, allowing tubby to enter the nucleus to bind DNA and regulate transcription. Some G-protein coupled receptors such as 5-HT2c may signal in part through tubby in addition to calcium-mediated pathways and protein-kinase signaling pathways. The identity of genes regulated by tubby and the mechanism by which tubby affects obesity remain to be explored.
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REFERENCES: Boggon,T.J., Shan, W.S., Santagata, S., Myers, S.C., and Shapiro, L. (1999) Implication of tubby proteins as transcription factors by structure-based functional analysis. Science 286(5447):2119-2125 Santagata, S., Boggon, T.J., Baird, C.L., Gomez, C.A., Zhao, J., Shan, W.S., Myszka, D.G., and Shapiro, L. (2001) G-Protein Signaling Through Tubby Proteins. Science 292 (5524):2041-2050
