title: Microphthalmia-associated transcription factor interactions with 14-3-3 modulate differentiation of committed myeloid precursors.
abstract: The microphthalmia-associated transcription factor (MITF) is required for terminal osteoclast differentiation and is a target for signaling pathways engaged by colony stimulating factor (CSF)-1 and receptor-activator of nuclear factor-kappaB ligand (RANKL). Work presented here demonstrates that MITF can shuttle from cytoplasm to nucleus dependent upon RANKL/CSF-1 action. 14-3-3 was identified as a binding partner of MITF in osteoclast precursors, and overexpression of 14-3-3 in a transgenic model resulted in increased cytosolic localization of MITF and decreased expression of MITF target genes. MITF/14-3-3 interaction was phosphorylation dependent, and Ser173 residue, within the minimal interaction region of amino acid residues 141-191, was required. The Cdc25C-associated kinase (C-TAK)1 interacted with an overlapping region of MITF. C-TAK1 increased MITF/14-3-3 complex formation and thus promoted cytoplasmic localization of MITF. C-TAK1 interaction was disrupted by RANKL/CSF-1 treatment. The results indicate that 14-3-3 regulates MITF activity by promoting the cytosolic localization of MITF in the absence of signals required for osteoclast differentiation. This work identifies a mechanism that regulates MITF activity in monocytic precursors that are capable of undergoing different terminal differentiation programs, and it provides a mechanism that allows committed precursors to rapidly respond to signals in the bone microenvironment to promote specifically osteoclast differentiation.
authors.affiliation: Department of Molecular and Cellular Biochemistry and the Comprehensive Cancer Center, The Ohio State University Medical Center, Columbus, OH 43210, USA.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Bronisz
authors.forename: Sudarshana M
authors.initials: SM
authors.lastname: Sharma
authors.forename: Rong
authors.initials: R
authors.lastname: Hu
authors.forename: Jakub
authors.initials: J
authors.lastname: Godlewski
authors.forename: Guri
authors.initials: G
authors.lastname: Tzivion
authors.forename: Kim C
authors.initials: KC
authors.lastname: Mansky
authors.forename: Michael C
authors.initials: MC
authors.lastname: Ostrowski
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism*; D000818:Animals; D019556:COS Cells; D002454:Cell Differentiation; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D015870:Gene Expression; D006801:Humans; D051379:Mice; D051739:Microphthalmia-Associated Transcription Factor / Q000737:chemistry / Q000378:metabolism*; D008954:Models, Biological; D023461:Myeloid Progenitor Cells / Q000166:cytology* / Q000378:metabolism*; D010010:Osteoclasts / Q000166:cytology; D010768:Phosphoserine / Q000378:metabolism; D011485:Protein Binding; D025941:Protein Interaction Mapping; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D021381:Protein Transport
chemical_list: D048948:14-3-3 Proteins; D051739:Microphthalmia-Associated Transcription Factor; D010768:Phosphoserine; D017346:Protein Serine-Threonine Kinases