FIGURE 7.

Proposed model for the role of the WNK1-TBC1D4 complex in regulating GLUT1 traffic in HEK293 cells. A fraction of GLUT1 is kept in an endosomal storage compartment in the cytosol. In the storage compartment TBC1D4 keeps Rab8A in the inactive GDP-bound conformation and prevents vesicle trafficking to the plasma membrane. Upon activation of WNK1, TBC1D4 becomes phosphorylated and associates with the phosphoprotein-binding 14-3-3 adaptor molecules so that the GAP activity of TBC1D4 is inhibited. Following Rab8A activation by GDP/GTP exchange, delivery of GLUT1-containing vesicles to the plasma membrane can occur promoting increased cellular glucose uptake. The upstream stimuli regulating WNK1 activation remain to be determined.