c-Kit triggers dual phosphorylations, which couple activation and degradation of the essential melanocyte factor Mi.
c-Kit triggers dual phosphorylations, which couple activation and degradation of the essential melanocyte factor Mi.
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DOI：
10.1101/gad.14.3.301
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发表时间：
2000-02
影响因子：
10.5
通讯作者：
Min Wu;T. Hemesath;Clifford M. Takemoto;M. Horstmann;Audrey G. Wells;E. Price;Daniel Z. Fisher
中科院分区：
文献类型：
--
作者：
Min Wu;T. Hemesath;Clifford M. Takemoto;M. Horstmann;Audrey G. Wells;E. Price;Daniel Z. Fisher
小眼球(Mi)是一种bHLHZip转录因子，对黑素细胞发育和出生后功能至关重要。根据突变的小鼠等位基因的表型，它被认为既能调节黑素细胞的分化特征，如色素沉着，又能调节增殖/存活。MI活性受至少两条信号通路控制。黑素细胞刺激素(MSH)通过cAMP升高促进Mi基因的转录，导致Mi持续上调数小时。C-Kit信号通过Mi的MAP激酶磷酸化上调Mi的功能，从而招募p300转录辅助激活因子。目前的研究表明，c-Kit信号在Mi上触发了两个磷酸化事件，这两个事件上调了反式激活潜能，同时靶向Mi进行泛素依赖的蛋白分解。特异的激活/降解信号来自丝氨酸73的MAPK/ERK靶向，而丝氨酸409作为p90RSK-1的底物。在这两个残基上不能磷酸化的双重突变体是非常稳定的，而且转录上是惰性的。这些c-Kit诱导的磷酸化将反式激活与蛋白酶体介导的降解结合在一起。因此，c-Kit信号触发了短暂的Mi激活和净Mi降解，而不是MSH信号后Mi表达的显著增加，这可能解释了该转录因子在调节黑素细胞增殖、存活和分化方面的功能多样性。
Microphthalmia (Mi) is a bHLHZip transcription factor that is essential for melanocyte development and postnatal function. It is thought to regulate both differentiated features of melanocytes such as pigmentation as well as proliferation/survival, based on phenotypes of mutant mouse alleles. Mi activity is controlled by at least two signaling pathways. Melanocyte-stimulating hormone (MSH) promotes transcription of the Mi gene through cAMP elevation, resulting in sustained Mi up-regulation over many hours. c-Kit signaling up-regulates Mi function through MAP kinase phosphorylation of Mi, thereby recruiting the p300 transcriptional coactivator. The current study reveals that c-Kit signaling triggers two phosphorylation events on Mi, which up-regulate transactivation potential yet simultaneously target Mi for ubiquitin-dependent proteolysis. The specific activation/degradation signals derive from MAPK/ERK targeting of serine 73, whereas serine 409 serves as a substrate for p90 Rsk-1. An unphosphorylatable double mutant at these two residues is at once profoundly stable and transcriptionally inert. These c-Kit-induced phosphorylations couple transactivation to proteasome-mediated degradation. c-Kit signaling thus triggers short-lived Mi activation and net Mi degradation, in contrast to the profoundly increased Mi expression after MSH signaling, potentially explaining the functional diversity of this transcription factor in regulating proliferation, survival, and differentiation in melanocytes.