IDENTIFICATION OF THE THYROID TRANSCRIPTION FACTOR-I AS A TARGET FOR RAT MST2 KINASE

Thyroid transcription factor-1 (TTF-1) is a homeodomain-containing tra nscription factor that is required for thyroid-specific expression of the thyroglobulin and thyroperoxidase genes as well as for lung-specif ic expression of the surfactant protein A, B, and C and the CC10 and t he HNF-3 alpha genes, TTF-1 is a phosphoprotein, and the phosphorylati on of TTF-1 has been studied already. However, the kinase(s) that coul d be responsible for this phosphorylation have not been known, In this paper we report the identification by in-gel kinase assay of a 56-kDa serine/threonine kinase that is able to phosphorylate TTF-1 in thyroi d cells. The cloning of this kinase revealed that we had identified th e rat homolog of the human MST2 kinase, The pathway in which human MST 2 functions is not known; however, it does not appear to involve eithe r mitogen-activated protein kinases such as Erk1 and Erk2 nor the stre ss-activated protein kinases such as JNK and p38, We show that the act ivity responsible for TTF-1 phosphorylation is constitutive in thyroid cells, Furthermore, we demonstrate that TTF-1 is phosphorylated in vi vo by rMST2 at the same residues that had been identified previously a s the major phosphorylation sites. Thus, TTF-1 represents the first id entified target of this class of protein kinases.