Differential NDR/LATS Interactions with the Human MOB Family Reveal a Negative Role for Human MOB2 in the Regulation of Human NDR Kinases
Differential NDR/LATS Interactions with the Human MOB Family Reveal a Negative Role for Human MOB2 in the Regulation of Human NDR Kinases
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DOI：
10.1128/mcb.00150-10
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发表时间：
2010-09-15
影响因子：
5.3
通讯作者：
Hergovich, Alexander
中科院分区：
文献类型：
--
作者：
Kohler, Reto S.;Schmitz, Debora;Hergovich, Alexander
MOB蛋白是控制重要细胞过程的信号通路的组成部分，所述细胞过程例如真核生物中的有丝分裂退出、中心体复制、凋亡和细胞增殖。人MOB B蛋白家族由6个不同的成员（人MOB 1A [hMOB 1A]、-1B、-2、-3A、-3B和-3C）组成，其中hMOB 1A/B由于其通过调节NDR/LATS激酶的假定肿瘤抑制功能而被研究得最好。其他MOB蛋白的作用不太明确。因此，我们在NDR/LATS结合的背景下表征了所有六种人MOB蛋白及其激活NDR/LATS激酶的能力。hMOB 3 A/B/C蛋白既不结合也不激活四种人NDR/LATS激酶中的任何一种。我们发现hMOB 2和hMOB 1A都与NDR 1的N端区域结合。然而，我们的数据表明，结合模式显着不同。我们的工作揭示了hMOB 2与hMOB 1A竞争NDR结合。与hMOB 1 A/B相反，hMOB 2与未磷酸化的NDR结合。此外，RNA干扰（RNAi）的hMOB 2的耗竭导致增加的NDR激酶活性。与这些发现一致，hMOB 2过表达干扰了NDR在死亡受体信号传导和中心体过度复制中的功能作用。总之，我们的数据表明，hMOB 2是一个负调节人的NDR激酶在生物化学和生物设置。
MOB proteins are integral components of signaling pathways controlling important cellular processes, such as mitotic exit, centrosome duplication, apoptosis, and cell proliferation in eukaryotes. The human MOB protein family consists of six distinct members (human MOB1A [hMOB1A], -1B, -2, -3A, -3B, and -3C), with hMOB1A/B the best studied due to their putative tumor-suppressive functions through the regulation of NDR/LATS kinases. The roles of the other MOB proteins are less well defined. Accordingly, we characterized all six human MOB proteins in the context of NDR/LATS binding and their abilities to activate NDR/LATS kinases. hMOB3A/B/C proteins neither bind nor activate any of the four human NDR/LATS kinases. We found that both hMOB2 and hMOB1A bound to the N-terminal region of NDR1. However, our data suggest that the binding modes differ significantly. Our work revealed that hMOB2 competes with hMOB1A for NDR binding. hMOB2, in contrast to hMOB1A/B, is bound to unphosphorylated NDR. Moreover, RNA interference (RNAi) depletion of hMOB2 resulted in increased NDR kinase activity. Consistent with these findings, hMOB2 overexpression interfered with the functional roles of NDR in death receptor signaling and centrosome overduplication. In summary, our data indicate that hMOB2 is a negative regulator of human NDR kinases in biochemical and biological settings.