Phosphorylation of serine 399 in LKB1 protein short form by protein kinase Cζ is required for its nucleocytoplasmic transport and consequent AMP-activated protein kinase (AMPK) activation

Huaiping Zhu, Cate M Moriasi, Miao Zhang, Yu Zhao, Ming-Hui Zou
Journal of Biological Chemistry 2013 June 7, 288 (23): 16495-505
Two splice variants of LKB1 exist: LKB1 long form (LKB1(L)) and LKB1 short form (LKB1(S)). In a previous study, we demonstrated that phosphorylation of Ser-428/431 (in LKB1(L)) by protein kinase Cζ (PKCζ) was essential for LKB1-mediated activation of AMP-activated protein kinase (AMPK) in response to oxidants or metformin. Paradoxically, LKB1S also activates AMPK although it lacks Ser-428/431. Thus, we hypothesized that LKB1(S) contained additional phosphorylation sites important in AMPK activation. Truncation analysis and site-directed mutagenesis were used to identify putative PKCζ phosphorylation sites in LKB1(S). Substitution of Ser-399 to alanine did not alter the activity of LKB1(S), but abolished peroxynitrite- and metformin-induced activation of AMPK. Furthermore, the phosphomimetic mutation (S399D) increased the phosphorylation of AMPK and its downstream target phospho-acetyl-coenzyme A carboxylase (ACC). PKCζ-dependent phosphorylation of Ser-399 triggered nucleocytoplasmic translocation of LKB1(S) in response to metformin or peroxynitrite treatment. This effect was ablated by pharmacological and genetic inhibition of PKCζ, by inhibition of CRM1 activity and by substituting Ser-399 with alanine (S399A). Overexpression of PKCζ up-regulated metformin-mediated phosphorylation of both AMPK (Thr-172) and ACC (Ser-79), but the effect was ablated in the S399A mutant. We conclude that, similar to Ser-428/431 (in LKB1(L)), Ser-399 (in LKB1(S)) is a PKCζ-dependent phosphorylation site essential for nucleocytoplasmic export of LKB1(S) and consequent AMPK activation.

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