title: The transcription factor FOXM1c is activated by protein kinase CK2, protein kinase A (PKA), c-Src and Raf-1.
abstract: The transcription factor FOXM1c possesses a very strong C-terminal TAD (transactivation domain), but full-length FOXM1c is only a weak transactivator because the TAD is completely inhibited by the auto-inhibitory N-terminus. The N-terminus blocks the TAD by directly binding to the TAD. Accordingly, FOXM1c deletion mutants without N-terminus are strong transactivators. Therefore, the question arises whether signals exist, which activate full-length FOXM1c by releasing the FOXM1c-TAD from its inhibition by the N-terminus. Indeed, full-length FOXM1c is strongly activated by protein kinase CK2 and PKA (protein kinase A). Both CK2 and PKA do not activate a FOXM1c deletion mutant without N-terminus demonstrating that the activation of FOXM1c by CK2 and PKA depends on the presence of the N-terminus. Consequently, CK2 and PKA activate FOXM1c by alleviating the inhibition of FOXM1c by its N-terminus. The presence of two potential CK2 phosphorylation sites and two potential PKA phosphorylation sites in the N-terminus of FOXM1c suggests that CK2 and PKA may activate FOXM1c through phosphorylation of the FOXM1c N-terminus. Thus, CK2 and PKA strongly activate full-length FOXM1c because they alleviate the repression of FOXM1c by its own auto-inhibitory N-terminus. Also c-Src activates full-length FOXM1c by relieving the inhibition of FOXM1c by its N-terminus. In contrast, Raf-1 activates FOXM1c independently of the FOXM1c N-terminus. In summary, this study shows for the first time that FOXM1c is activated by the four kinases CK2, PKA, c-Src and Raf-1.
authors.affiliation: Institute of Molecular Biology, Medical School Hannover, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany. iwiwiwi@web.de
authors.forename: Inken
authors.initials: I
authors.lastname: Wierstra
mesh_terms: D000081247:CSK Tyrosine-Protein Kinase; D047390:Casein Kinase II / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics / Q000378:metabolism*; D019061:src-Family Kinases
chemical_list: C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; D047390:Casein Kinase II; D019908:Proto-Oncogene Proteins c-raf; D017868:Cyclic AMP-Dependent Protein Kinases