Regulator of G protein signaling RGS3T is localized to the nucleus and induces apoptosis

RGS3 belongs to a family of the regulators of G protein signaling (RGS). We previously demonstrated that cytosolic RGS3 translocates to the membrane t o inhibit Gq/11 signaling (Dulin, N. O., Sorokin, A., Reed, E., Elliott, S. , Kehrl, J., and Dunn, M. J. (1999) Mol. Cell. Biol. 19, 714-723). This stu dy examines the properties of a recently identified truncated variant terme d RGS3T. Both RGS3 and RGS3T bound to endogenous G alpha(q/11) and inhibite d endothelin-1-stimulated calcium mobilization and mitogen-activated protei n kinase activity to a similar extent. However, unlike cytosolically locali zed RGS3, RGS3T was found predominantly in the nucleus and partially in the plasma membrane. Furthermore, RGS3T, but not RGS3, caused cell rounding an d membrane blebbing. Finally, 44% of RGS3T-transfected cells underwent apop tosis after serum withdrawal, which was significantly higher than that of R GS3-transfected cells (7%). Peptide sequence analysis revealed two potentia l nuclear localization signal (NLS) sequences in RGS3T. Further truncation of the RGS3T N terminus containing putative NLSs resulted in a significant reduction of nuclear versus cytoplasmic staining of the protein. Moreover, this truncated RGS3T no longer induced apoptosis. In summary, RGS3 and its truncated variant RGS3T are similar in their ability to inhibit G(q/11) sig naling but are different in their intracellular distribution. These data su ggest that, in addition to being a GTPase-activating protein, RGS3T has oth er distinct functions in the nucleus of the cell.