Retrograde signaling is regulated by the dynamic interaction between Rtg2p and Mks1p.

Activation of retrograde signaling (RS) by mitochondrial dysfunction or by inhibition of TOR kinases in yeast results in nuclear accumulation of the transcription factors, Rtg1p and Rtg3p. This process requires Rtg2p, a novel cytoplasmic protein with an N-terminal ATP binding domain. We show that Rtg2p controls RS by reversibly binding a negative regulator, Mks1p. The inhibitory form of Mks1p is phosphorylated and complexed with the 14-3-3 proteins, Bmh1p and Bmh2p, which are also negative regulators of RS. A hypophosphorylated form of Mks1p bound to Rtg2p is inactive. Point mutations in the Rtg2p ATP binding domain simultaneously block RS and Mks1p-Rtg2p interaction. We propose that activation of RS via mitochondrial dysfunction and TOR inhibition intersect at the Rtg2p-Mks1p switch.