We show that Rap2, a member of the Ras GTPase family, positively regulates Activin/Nodal signaling activity by controlling the trafficking of its receptors. In the absence of ligand activation, Rap2 directs internalized Activin/Nodal receptors into a recycling pathway, thereby preventing their degradation and maintaining their levels on the cell surface. Upon ligand activation, Rap2 no longer promotes receptor recycling but delays its turnover. In both cases, Rap2 contributes to upregulation of signaling activity by antagonizing Smad7. In addition, we found that the efficiency of Activin/Nodal receptor recycling is different between dorsal and ventral halves of Xenopus early embryo, which results from the asymmetric expression of Rap2 and Smad7. Consequently, they regulate cell responsiveness to ligands and the spatiotemporally dynamic activation of Smad2 along the dorsoventral axis of the embryo. Therefore, these findings suggest a molecular basis for the regulation of signaling activity and embryonic patterning by Activin/Nodal receptor trafficking.
Bibliographical noteFunding Information:
We thank K. Cho, M. Whitman, J. Christian, E-H. Jho, and M.A Scidmore for gifts of reagents. We are also grateful to the other members of our laboratory for critical comment and support. This work was supported by the Advanced Basic Research Laboratory Program (R14-2002-012-01001-0) and Pure Basic Research Group (070-2005-C00115) of the KRF, and Brain Korea 21 project.