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Lineage-specific signaling in melanocytes. C-kit stimulation recruits p300/CBP to microphthalmia
E R Price1, H F Ding, T Badalian
1Pediatric Hematology/Oncology, Dana Farber Cancer Research Institute and Harvard Medical School, Boston, Massachusetts 02115, USA.
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.
Insights
Steel factor and c-Kit signaling phosphorylate Microphthalmia (Mi), a key transcription factor. This phosphorylation enhances Mi
Area of Science:
- Cellular signaling pathways
- Molecular biology
- Developmental biology
Background:
- Melanocyte development relies on the Steel factor/c-Kit pathway.
- Microphthalmia (Mi) is a crucial lineage-restricted transcription factor for melanocytes.
- The precise mechanism of Mi activation by c-Kit signaling remains unclear.
Purpose of the Study:
- To elucidate how mitogen-activated protein kinase (MAPK) signaling activates the Microphthalmia (Mi) transcription factor.
- To investigate the role of Mi phosphorylation in its transcriptional activity.
Main Methods:
- Investigated the effect of MAPK-mediated phosphorylation on Mi nuclear localization, DNA binding, and dimerization.
- Assessed the interaction between phosphorylated Mi and transcriptional coactivators.
- Examined the impact of coactivator association on Mi-dependent transcriptional activity.
Main Results:
- MAPK phosphorylation of Mi does not significantly alter its nuclear localization, DNA binding, or dimerization.
- The transcriptional coactivator p300/CBP selectively binds to MAPK-phosphorylated Mi.
- p300/CBP coactivation of Mi is dependent on this specific phosphorylation event.
Conclusions:
- Signal-responsive phosphorylation of Mi by the Steel factor/c-Kit pathway regulates coactivator recruitment.
- This mechanism modulates Mi transcriptional activity, impacting melanocyte lineage development.
- Mi regulation by coactivator recruitment is analogous to that of CREB.