STRADα regulates LKB1 localization by blocking access to importin-α, and by association with Crm1 and exportin-7
STRADα regulates LKB1 localization by blocking access to importin-α, and by association with Crm1 and exportin-7
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DOI：
10.1091/mbc.e07-05-0454
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发表时间：
2008-04-01
影响因子：
3.3
通讯作者：
Macara, Ian G.
中科院分区：
文献类型：
--
作者：
Dorfman, Julia;Macara, Ian G.
LKB1是一种丝氨酸/苏氨酸激酶，调节细胞的极性、代谢和细胞生长。LKB1的活性和细胞分布由辅因子STRADα和MO25决定。STRADα诱导LKB1从胞核到细胞质的重新定位，并刺激其催化活性。MO25稳定了Stradα/LKB1的相互作用。我们研究了LKB1在其辅因子作用下的核质转运机制。虽然LKB1是通过Importin-α/beta进入细胞核的，但STRADα和MO25在细胞核和细胞质之间被动扩散。STRADα诱导LKB1核质穿梭。STRADα通过充当LKB1与出口蛋白CRM1和出口蛋白7之间的适配器，促进LKB1的核出口。STRAD-α通过与Importin-α竞争结合LKB1来抑制LKB1的进口。MO25稳定LKB1-Stradα复合体，但不促进其核质穿梭。值得注意的是，STRADα亚型与STRADβ亚型不同，它在负责与出口受体相互作用的N-末端和C-末端区域，不能有效地将LKB1从细胞核重新定位到细胞质。这些结果证实了一种控制LKB1定位的多因素机制，并提示Stradβ-LKB1复合体可能在细胞核中具有独特的功能。
LKB1, a serine/threonine kinase, regulates cell polarity, metabolism, and cell growth. The activity and cellular distribution of LKB1 are determined by cofactors, STRAD alpha and MO25. STRAD alpha induces relocalization of LKB1 from the nucleus to the cytoplasm and stimulates its catalytic activity. MO25 stabilizes the STRAD alpha/LKB1 interaction. We investigated the mechanism of nucleocytoplasmic transport of LKB1 in response to its cofactors. Although LKB1 is imported into the nucleus by importin-alpha/beta, STRAD alpha and MO25 passively diffuse between the nucleus and the cytoplasm. STRAD alpha induces nucleocytoplasmic shuttling of LKB1. STRAD alpha facilitates nuclear export of LKB1 by serving as an adaptor between LKB1 and exportins CRM1 and exportin7. STRAD alpha inhibits import of LKB1 by competing with importin-alpha for binding to LKB1. MO25 stabilizes the LKB1-STRAD alpha complex but it does not facilitate its nucleocytoplasmic shuttling. Strikingly, the STRAD alpha, isoform which differs from STRAD beta in the N- and C-terminal domains that are responsible for interaction with export receptors, does not efficiently relocalize LKB1 from the nucleus to the cytoplasm. These results identify a multifactored mechanism to control LKB1 localization, and they suggest that the STRAD beta-LKB1 complex might possess unique functions in the nucleus.