Akt blocks the tumor suppressor activity of LKB1 by promotingphosphorylation-dependent nuclear retention through 14-3-3proteins

American Journal of Translational Research

Aimin Xu¹  Chi-Ming Che¹  Ling Liu¹  Yu Wang¹  Fung-Ming Siu¹ 

关键词: Akt kinase;    14-3-3;    LKB1;    nuclear/cytoplasmic shuttling;    tumorigenesis;   

DOI  :  

学科分类：医学（综合）

来源: e-Century Publishing Corporation

【 摘 要 】

The survival kinase Akt and the tumor suppressor LKB1 elicit opposite effects oncell proliferation and tumorigenesis. The present study demonstrates that Aktacts as an upstream kinase of LKB1 to promote the phosphorylation at Ser334 andfacilitate its binding to 14-3-3 proteins, resulting in a decreased interactionwith STE20-related adaptor protein α (STRADα) and an enhancednuclear accumulation of LKB1. The S334A mutant of LKB1 exhibits impaired bindingwith 14-3-3 proteins and is localized predominantly in the cytoplasm, whereasthe phosphorylation-mimic mutant, S334D, is sequestrated in the nuclei andunable to elicit the tumor suppressor function. On the other hand, S334A exertsmore potent activity than wild type LKB1 in inhibiting the breast cancer cellproliferation and tumor growth in mice. These findings suggest that Akt blocksthe anti-growth signal of LKB1 by triggering a phosphorylation-dependent nuclearsequestration of LKB1 through 14-3-3 proteins.

【 授权许可】

Unknown