Gαo mediates WNT-JNK signaling through Dishevelled 1 and 3, RhoA family members, and MEKK 1 and 4 in mammalian cells
Gαo mediates WNT-JNK signaling through Dishevelled 1 and 3, RhoA family members, and MEKK 1 and 4 in mammalian cells
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DOI：
10.1242/jcs.021964
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发表时间：
2008-01-15
影响因子：
4
通讯作者：
Malbon, Craig C.
中科院分区：
文献类型：
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作者：
Bikkavilli, Rama Kamesh;Feigin, Michael E.;Malbon, Craig C.
在果蝇中，由卷曲蛋白（Frizzled）和蓬乱蛋白（Dishevelled）介导的 Jun N - 末端激酶（JNK）的激活导致与平面细胞极性相关的信号传导。在哺乳动物细胞中对WNT - JNK平面细胞极性进行了生化描述，利用全能的小鼠F9畸胎瘤细胞，该细胞通过卷曲蛋白 - 1对WNT3a作出反应。经典的WNT - β - 连环蛋白信号通路需要Gα(o)和Gα(q)异源三聚体G蛋白，然而我们表明WNT - JNK信号传导仅需要Gα(o)蛋白。通过使用蓬乱蛋白拮抗剂Dapper1（DACT1）进行的上位性实验确定，Gα(o)通过所有三种蓬乱蛋白异构体向下游传递信号。抑制蓬乱蛋白 - 1或蓬乱蛋白 - 3，但不抑制蓬乱蛋白 - 2，会消除WNT3a对JNK的激活。小GTP酶RhoA、Rac1和Cdc42的激活在蓬乱蛋白的下游起作用，与MEKK 1/MEKK 4依赖的级联反应相关联，并进一步激活JNK。JNK的化学抑制剂（SP600125），而不是p38的抑制剂（SB203580），可阻断WNT3a对JNK的激活，然而这两种抑制剂都会减弱WNT3a - β - 连环蛋白通路。这些数据揭示了WNT3a敏感通路中共同的和独特的信号元件，突显了从WNT3a - JNK到WNT3a - β - 连环蛋白信号传导的串扰。
In Drosophila, activation of Jun N-terminal Kinase (JNK) mediated by Frizzled and Dishevelled leads to signaling linked to planar cell polarity. A biochemical delineation of WNT-JNK planar cell polarity was sought in mammalian cells, making use of totipotent mouse F9 teratocarcinoma cells that respond to WNT3a via Frizzled-1. The canonical WNT-beta-catenin signaling pathway requires both G alpha(o) and G alpha(q) heterotrimeric G-proteins, whereas we show that WNT-JNK signaling requires only G alpha(o) protein. G alpha(o) propagates the signal downstream through all three Dishevelled isoforms, as determined by epistasis experiments using the Dishevelled antagonist Dapper1 (DACT1). Suppression of either Dishevelled-1 or Dishevelled-3, but not Dishevelled-2, abolishes WNT3a activation of JNK. Activation of the small GTPases RhoA, Rac1 and Cdc42 operates downstream of Dishevelled, linking to the MEKK 1/MEKK 4-dependent cascade, and on to JNK activation. Chemical inhibitors of JNK (SP600125), but not p38 (SB203580), block WNT3a activation of JNK, whereas both the inhibitors attenuate the WNT3a-beta-catenin pathway. These data reveal both common and unique signaling elements in WNT3a-sensitive pathways, highlighting crosstalk from WNT3a-JNK to WNT3a-beta-catenin signaling.