MO25α/β interact with STRADα/β enhancing their ability to bind, activate and localize LKB1 in the cytoplasm
MO25α/β interact with STRADα/β enhancing their ability to bind, activate and localize LKB1 in the cytoplasm
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DOI：
10.1093/emboj/cdg490
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发表时间：
2003-10-01
期刊：
影响因子：
11.4
通讯作者：
Alessi, DR
中科院分区：
文献类型：
--
作者：
Boudeau, J;Baas, AF;Alessi, DR
LKB1蛋白激酶的突变导致遗传性Peutz Jeghers癌症综合征。LKB1与调节细胞增殖和极性有关，尽管人们对该酶是如何调控的知之甚少。我们最近发现，LKB1是通过与STRADAlpha相互作用而被激活的，STRADAlpha是一种催化缺陷的假激酶。在这里，我们证明了内源性LKB1-STRADAlpha复合体通过MO25pha与STRADAlpha的最后三个残基相互作用，与一种功能未知的蛋白质MO25Alpha相关。MO25pha和STRADpha将LKB1锚定在细胞质中，不包括在细胞核中。此外，MO25α在体内促进LKB1-STRADAlpha复合体的形成，刺激LKB1的催化活性接近10倍。我们证明了相关的STRADbeta和MO25beta亚型也能够稳定活性络合物中的LKB1，并且有可能分离与STRAD和MO25亚型结合的LKB1络合物，其中亚基以等摩尔量存在。我们的结果表明，MO25可能作为LKB1-Strad复合体的支架成分，在调节LKB1的活性和细胞定位方面发挥关键作用。
Mutations in the LKB1 protein kinase result in the inherited Peutz Jeghers cancer syndrome. LKB1 has been implicated in regulating cell proliferation and polarity although little is known about how this enzyme is regulated. We recently showed that LKB1 is activated through its interaction with STRADalpha, a catalytically deficient pseudokinase. Here we show that endogenous LKB1-STRADalpha complex is associated with a protein of unknown function, termed MO25alpha, through the interaction of MO25alpha with the last three residues of STRADalpha. MO25alpha and STRADalpha anchor LKB1 in the cytoplasm, excluding it from the nucleus. Moreover, MO25alpha enhances the formation of the LKB1-STRADalpha complex in vivo, stimulating the catalytic activity of LKB1 similar to10-fold. We demonstrate that the related STRADbeta and MO25beta isoforms are also able to stabilize LKB1 in an active complex and that it is possible to isolate complexes of LKB1 bound to STRAD and MO25 isoforms, in which the subunits are present in equimolar amounts. Our results indicate that MO25 may function as a scaffolding component of the LKB1-STRAD complex and plays a crucial role in regulating LKB1 activity and cellular localization.