title: Lineage-specific signaling in melanocytes. C-kit stimulation recruits p300/CBP to microphthalmia.
abstract: During melanocyte development, the cytokine Steel factor activates its receptor c-Kit, initiating a signal transduction cascade, which is vital for lineage determination via unknown downstream nuclear targets. c-Kit has recently been found to trigger mitogen-activated protein kinase-mediated phosphorylation of Microphthalmia (Mi), a lineage-restricted transcription factor, which, like Steel factor and c-Kit, is essential for melanocyte development. This cascade results in increased Mi-dependent transcriptional reporter activity. Here we examine the mechanism by which Mi is activated by this pathway. Phosphorylation does not significantly alter Mi's nuclear localization, DNA binding, or dimerization. However, the transcriptional coactivator p300/CBP selectively associates with mitogen-activated protein kinase-phosphorylated Mi, even under conditions in which non-MAPK phospho-Mi is more abundant. Moreover, p300/CBP coactivates Mi transcriptional activity in a manner dependent upon this phosphorylation. Mi thus joins CREB as a transcription factor whose signal-responsive phosphorylation regulates coactivator recruitment, in this case modulating lineage development in melanocytes.
authors.affiliation: Pediatric Hematology/Oncology, Dana Farber Cancer Research Institute and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: E R
authors.initials: ER
authors.lastname: Price
authors.forename: H F
authors.initials: HF
authors.lastname: Ding
authors.forename: T
authors.initials: T
authors.lastname: Badalian
authors.forename: S
authors.initials: S
authors.lastname: Bhattacharya
authors.forename: C
authors.initials: C
authors.lastname: Takemoto
authors.forename: T P
authors.initials: TP
authors.lastname: Yao
authors.forename: T J
authors.initials: TJ
authors.lastname: Hemesath
authors.forename: D E
authors.initials: DE
authors.lastname: Fisher
mesh_terms: D000818:Animals; D050882:CREB-Binding Protein; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D006224:Cricetinae; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D019281:Dimerization; D050881:E1A-Associated p300 Protein; D004789:Enzyme Activation; D006801:Humans; D008544:Melanocytes / Q000502:physiology*; D051379:Mice; D051739:Microphthalmia-Associated Transcription Factor; D009687:Nuclear Proteins / Q000502:physiology*; D010766:Phosphorylation; D011485:Protein Binding; D019009:Proto-Oncogene Proteins c-kit / Q000502:physiology; D011817:Rabbits; D015398:Signal Transduction; D019089:Stem Cell Factor / Q000502:physiology; D015534:Trans-Activators / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
chemical_list: D004268:DNA-Binding Proteins; C497234:MITF protein, human; D051739:Microphthalmia-Associated Transcription Factor; C497235:Mitf protein, mouse; D009687:Nuclear Proteins; D019089:Stem Cell Factor; D015534:Trans-Activators; D014157:Transcription Factors; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; C494364:Crebbp protein, mouse; D050881:E1A-Associated p300 Protein; C494361:Ep300 protein, mouse; D019009:Proto-Oncogene Proteins c-kit; D017871:Calcium-Calmodulin-Dependent Protein Kinases