| Expression of an activated form of Raf ( Raf BXB ) also inhibits TTF 1 function to a similar extent , while the MEK inhibitors U 0126 and PD 98059 partially relieve Ras mediated inactivation of TTF 1 , suggesting that the extracellular signal regulated kinase ( ERK ) pathway is involved in this process . ^^^ Indeed , ERK directly phosphorylates TTF 1 at three serine residues , and concomitant mutation of these serines to alanines completely abolishes ERK mediated phosphorylation both in vitro and in vivo . ^^^ Since activation of the Raf / MEK / ERK pathway accounts for only part of the activity elicited by oncogenic Ras on TTF 1 , other downstream pathways are likely to be involved in this process . ^^^ However , a poorly characterized Ras mutant , V12N38 Ras , can partially repress TTF 1 transcriptional activity through an ERK independent pathway . ^^^ Our data indicate that the Raf / MEK / ERK cascade may act in concert with an as yet uncharacterized signaling pathway activated by V12N38 Ras to repress TTF 1 function and ultimately to inhibit thyroid cell differentiation . . ^^^ |