Figure 4. Integrated regulation of NUAK expression by TGFβ and HIPPO pathways.

Ligand- activated TGFβR phosphorylates SMAD2 & SMAD3, which then complex along with SMAD4 and translocate to the nucleus. SMAD2/3 complexes directly bind an enhancer on the NUAK2 gene to drive expression. Both NUAKs inhibit HIPPO kinases LATS1/LATS2 by direct phosphorylation and potentially via inhibition of PP1β-dependent dephosphorylation, allowing unphosphorylated HIPPO effectors YAP1 and TAZ to translocate to the nucleus and activate TEAD-dependent gene expression. Expression of both NUAKs is directly regulated by YAP/TAZ/TEAD.