ArticleThe Journal of biological chemistry2013
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.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 27 citations in OpenAlex.
- Deficiency of GCN5 exacerbates pulmonary fibrosis by disrupting the LKB1-AMPK pathway.Cell communication and signaling : CCS · 2026Article
- LKB1 biology: assessing the therapeutic relevancy of LKB1 inhibitors.Cell communication and signaling : CCS · 2024Review
- Liver Kinase B1 Functions as a Regulator for Neural Development and a Therapeutic Target for Neural Repair.Cells · 2022Review
- Restoration of atypical protein kinase C ζ function in autosomal dominant polycystic kidney disease ameliorates disease progression.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Bioactive compounds from Artemisia dracunculus L. activate AMPK signaling in skeletal muscle.Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie · 2021Article
- Genomic Characterization of HPV-related and Gastric-type Endocervical Adenocarcinoma: Correlation With Subtype and Clinical Behavior.International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists · 2020Article
- Metformin attenuates the effect of Staphylococcus aureus on airway tight junctions by increasing PKCζ-mediated phosphorylation of occludin.Journal of cellular and molecular medicine · 2019Article
- Upregulation of liver kinase B1 predicts poor prognosis in hepatocellular carcinoma.International journal of oncology · 2018Article
- AMPK Function in Mammalian Spermatozoa.International journal of molecular sciences · 2018Review
- PAR3-PAR6-atypical PKC polarity complex proteins in neuronal polarization.Cellular and molecular life sciences : CMLS · 2018Review
- Review
- Pioglitazone stabilizes atherosclerotic plaque by regulating the Th17/Treg balance in AMPK-dependent mechanisms.Cardiovascular diabetology · 2017Article
- Metformin inhibits the development, and promotes the resensitization, of treatment-resistant breast cancer.PloS one · 2017Article
- Two PTP receptors mediate CSPG inhibition by convergent and divergent signaling pathways in neurons.Scientific reports · 2016Article
- Extracellular lumican augments cytotoxicity of chemotherapy in pancreatic ductal adenocarcinoma cells via autophagy inhibition.Oncogene · 2016Article
- Regulation and function of AMPK in physiology and diseases.Experimental & molecular medicine · 2016Review
- Conditional knockout of polarity complex (atypical) PKCι reveals an anti-inflammatory function mediated by NF-κB.Molecular biology of the cell · 2016Article
- AMP-activated protein kinase contributes to zinc-induced neuronal death via activation by LKB1 and induction of Bim in mouse cortical cultures.Molecular brain · 2016Article
- Convergence of IPMK and LKB1-AMPK signaling pathways on metformin action.Molecular endocrinology (Baltimore, Md.) · 2014Article
Corrections and comments
- Erratum issued
Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
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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