MKP-3 has essential roles as a negative regulator of the Ras/mitogen-activated protein kinase pathway during Drosophila development
MKP-3 has essential roles as a negative regulator of the Ras/mitogen-activated protein kinase pathway during Drosophila development
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DOI：
10.1128/mcb.24.2.573-583.2004
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发表时间：
2004-01-01
影响因子：
5.3
通讯作者：
Chung, JK
中科院分区：
文献类型：
--
作者：
Kim, M;Cha, GH;Chung, JK
丝裂原活化蛋白激酶（MAPK）磷酸酶3（MKP-3）是Ras/细胞外信号调节激酶（ERK）-MAPK信号通路中的负调节因子，其负责发育期间的细胞命运决定和增殖。然而，MKP-3的生理作用和MKP-3在体内调节Ras/果蝇ERK（DERK）信号传导的机制尚未确定。在这里，我们证明，果蝇MKP-3（DMKP-3）是至关重要的参与细胞分化，增殖和基因表达，通过抑制Ras/DERK途径，通过DMKP-3的N-末端ERK结合结构域特异性结合DERK。DMKP-3的过表达减少了光感受器细胞的数量，抑制了翅静脉的分化。相反，DMKP-3亚型突变体表现出额外的感光细胞和翅静脉，其无效突变体表现出惊人的表型，如胚胎死亡和卵子发生严重缺陷。所有这些表型与DERK/rl的功能获得性突变体的表型高度相似。DMKP-3和Ras/DERK途径之间的功能相互作用通过DMKP-3功能丧失突变体或过表达转基因果蝇和Ras/DERK途径的各种突变体之间的遗传相互作用进一步证实。总的来说，这些数据提供了直接证据，证明DMKP-3对于果蝇发育期间DERK信号活性的调节是不可或缺的。
Mitogen-activated protein kinase (MAPK) phosphatase 3 (MKP-3) is a well-known negative regulator in the Ras/extracellular signal-regulated kinase (ERK)-MAPK signaling pathway responsible for cell fate determination and proliferation during development. However, the physiological roles of MKP-3 and the mechanism by which MKP-3 regulates Ras/Drosophila ERK (DERK) signaling in vivo have not been determined. Here, we demonstrated that Drosophila MKP-3 (DMKP-3) is critically involved in cell differentiation, proliferation, and gene expression by suppressing the Ras/DERK pathway, specifically binding to DERK via the N-terminal ERK-binding domain of DMKP-3. Overexpression of DMKP-3 reduced the number of photoreceptor cells and inhibited wing vein differentiation. Conversely, DMKP-3 hypomorphic mutants exhibited extra photoreceptor cells and wing veins, and its null mutants showed striking phenotypes, such as embryonic lethality and severe defects in oogenesis. All of these phenotypes were highly similar to those of the gain-of-function mutants of DERK/rl. The functional interaction between DMKP-3 and the Ras/DERK pathway was further confirmed by genetic interactions between DMKP-3 loss-of-function mutants or overexpressing transgenic flies and various mutants of the Ras/DERK pathway. Collectively, these data provide the direct evidences that DMKP-3 is indispensable to the regulation of DERK signaling activity during Drosophila development.