Baas A F, Boudeau J, Sapkota G P, Smit L, Medema R, Morrice N A, Alessi D R, Clevers H C
Hubrecht Laboratory, Centre for Biomedical Genetics, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands.
EMBO J. 2003 Jun 16;22(12):3062-72. doi: 10.1093/emboj/cdg292.
The LKB1 gene encodes a serine/threonine kinase mutated in Peutz-Jeghers cancer syndrome. Despite several proposed models for LKB1 function in development and in tumour suppression, the detailed molecular action of LKB1 remains undefined. Here, we report the identification and characterization of an LKB1-specific adaptor protein and substrate, STRAD (STe20 Related ADaptor). STRAD consists of a STE20- like kinase domain, but lacks several residues that are indispensable for intrinsic catalytic activity. Endogenous LKB1 and STRAD form a complex in which STRAD activates LKB1, resulting in phosphorylation of both partners. STRAD determines the subcellular localization of wild-type, but not mutant LKB1, translocating it from nucleus to cytoplasm. One LKB1 mutation previously identified in a Peutz-Jeghers family that does not compromise its kinase activity is shown here to interfere with LKB1 binding to STRAD, and hence with STRAD-dependent regulation. Removal of endogenous STRAD by siRNA abrogates the LKB1-induced G(1) arrest. Our results imply that STRAD plays a key role in regulating the tumour suppressor activities of LKB1.
LKB1基因编码一种丝氨酸/苏氨酸激酶，该激酶在黑斑息肉综合征中发生突变。尽管已经提出了几种关于LKB1在发育和肿瘤抑制中的功能模型，但LKB1具体的分子作用仍不明确。在此，我们报告了一种LKB1特异性衔接蛋白及底物STRAD（STe20相关衔接蛋白）的鉴定与特性。STRAD包含一个类似STE20的激酶结构域，但缺少一些对内在催化活性必不可少的残基。内源性LKB1和STRAD形成复合物，其中STRAD激活LKB1，导致两者均发生磷酸化。STRAD决定野生型而非突变型LKB1的亚细胞定位，使其从细胞核转运至细胞质。在此显示，先前在一个黑斑息肉家族中鉴定出的一个不影响其激酶活性的LKB1突变，会干扰LKB1与STRAD的结合，进而干扰STRAD依赖性调节。通过小干扰RNA去除内源性STRAD可消除LKB1诱导的G1期阻滞。我们的结果表明，STRAD在调节LKB1的肿瘤抑制活性中起关键作用。
