Net1 is an oncoprotein that acts as a RhoA-specific guanine nucleotide exchange factor (GEF) to enhance cancer cell migration and invasion. Net1 has two nuclear localisation sequences in its N-terminus that function to localise Net1 predominantly to the nucleus; its roles there, however, are unclear. In their Research Article on page 3072, Qiang Wang and colleagues investigate the functions of nuclear Net1 using various gain- and loss-of-function experiments in both zebrafish embryos and mammalian cells. The authors show that zebrafish net1 is essential for mesendoderm formation, and promotes that formation by upregulating Nodal signalling. Moreover, nuclear Net1 enhances Nodal signalling, as well as mesendoderm formation, independently of its GEF activity. Net1 also interacts with nuclear Smad2 independently of its GEF activity, and this interaction facilitates the recruitment of p300 to the transcriptional complex. The authors previously described a role for Net1 in dorsal fate specification in the early zebrafish embryo, and the results shown here demonstrate that Net1 has an additional role in mesendoderm formation by acting as a potentiator of Nodal signalling.
