AJTR Copyright © 2009-All rights reserved. Published by e-Century Publishing Corporation, Madison, WI 53711
Am J Transl Res 2012;4(2):175-186

Original Article
Akt blocks the tumor suppressor activity of LKB1 by promoting
phosphorylation-dependent nuclear retention through 14-3-3 proteins

Ling Liu, Fung-Ming Siu, Chi-Ming Che, Aimin Xu, Yu Wang

Department of Medicine; Department of Pharmacology and Pharmacy; Department of Chemistry and Open
Laboratory of Chemical Biology of the Institute of Molecular Technology for Drug Discovery and Synthesis, The
University of Hong Kong, Hong Kong, China

Received March 14, 2012; accepted March 25, 2012; Epub April 10, 2012; Published April 30, 2012

Abstract: The survival kinase Akt and the tumor suppressor LKB1 elicit opposite effects on cell proliferation and
tumorigenesis. The present study demonstrates that Akt acts as an upstream kinase of LKB1 to promote the
phosphorylation at Ser334 and facilitate its binding to 14-3-3 proteins, resulting in a decreased interaction with
STE20-related adaptor protein α (STRADα) and an enhanced nuclear accumulation of LKB1. The S334A mutant
of LKB1 exhibits impaired binding with 14-3-3 proteins and is localized predominantly in the cytoplasm, whereas
the phosphorylation-mimic mutant, S334D, is sequestrated in the nuclei and unable to elicit the tumor
suppressor function. On the other hand, S334A exerts more potent activity than wild type LKB1 in inhibiting the
breast cancer cell proliferation and tumor growth in mice. These findings suggest that Akt blocks the anti-growth
signal of LKB1 by triggering a phosphorylation-dependent nuclear sequestration of LKB1 through 14-3-3 proteins.

Keywords: Akt kinase, 14-3-3, LKB1, nuclear/cytoplasmic shuttling, tumorigenesis

Address all correspondence to:
Dr. Yu Wang
Level 2, Laboratory Block, 21 Sassoon Road
Pokfulam, Hong Kong, China.
Tel: 852 28192864; Fax: 852 28170859
E-mail: yuwanghk@hku.hk;

Dr. Aimin Xu
Level 8, Laboratory Block, 21 Sassoon Rd
Pokfulam, Hong Kong, China.
Tel: 852 28199754; Fax: 852 28162095
E-mail: amxu@hku.hk