MO25alpha/beta interact with STRADalpha/beta enhancing their ability to bind, activate and localize LKB1 in the cytoplasm.
MO25alpha/beta interact with STRADalpha/beta enhancing their ability to bind, activate and localize LKB1 in the cytoplasm.
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发表时间：
2003
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通讯作者：
J. Boudeau;A. Baas;M. Deák;N. Morrice;A. Kieloch;M. Schutkowski;A. Prescott;H. Clevers;D. Alessi
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作者：
J. Boudeau;A. Baas;M. Deák;N. Morrice;A. Kieloch;M. Schutkowski;A. Prescott;H. Clevers;D. Alessi
LKB1 蛋白激酶突变会导致遗传性 Peutz Jeghers 癌症综合征。 LKB1 与调节细胞增殖和极性有关，尽管人们对这种酶的调节方式知之甚少。我们最近表明，LKB1 通过与 STRADalpha（一种催化缺陷的假激酶）相互作用而被激活。在这里，我们证明内源性 LKB1-STRADalpha 复合物通过 MO25alpha 与 STRADalpha 的最后三个残基的相互作用与未知功能的蛋白质（称为 MO25alpha）相关。 MO25alpha 和 STRADalpha 将 LKB1 锚定在细胞质中，将其排除在细胞核之外。此外，MO25alpha 还能增强体内 LKB1-STRADalpha 复合物的形成，将 LKB1 的催化活性刺激约 10 倍。我们证明相关的 STRADbeta 和 MO25beta 同工型也能够稳定活性复合物中的 LKB1，并且可以分离与 STRAD 和 MO25 同工型结合的 LKB1 复合物，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 复合物的支架组件，在调节 LKB1 活性和细胞定位中发挥着至关重要的作用。
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 approximately 10-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.