title: MLK3 phophorylates AMPK independently of LKB1.
abstract: Emerging evidence has shown that cellular energy metabolism is regulated by the AMPK and MLK3-JNK signaling pathways, but the functional link between them remains to be determined. The present study aimed to explore the crosstalk between MLK3 and AMPK. We found that both JNK and AMPK were phosphorylated at their activation sites by TNF-α, Anisomycin, H2O2 and sorbitol. Interestingly, sorbitol stimulated phosphorylation of AMPK at T172 in LKB1-deficient cells. Following the screening of more than 100 kinases, we identified that MLK3 induced phosphorylation of AMPK at T172. Our in vitro analysis further revealed that MLK3-mediated phosphorylation of AMPK at T172 was independent of AMP, but addition of AMP caused a mobility shift of AMPK, an indication of autophosphorylation, suggesting that AMP binding and phosphorylation of T172 leads to maximal activation of AMPK. GST-pull down assays showed a direct interaction between AMPKα1 subunit and MLK3. Altogether, our results indicate that MLK3 serves as a common upstream kinase of AMPK and JNK and functions as a direct upstream kinase for AMPK independent of LKB1.
authors: Research Institute of Digestive Diseases, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, China.
authors: Lingyu
authors: L
authors: Luo
authors: Graduate Program, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330006, China.
authors: Shanshan
authors: S
authors: Jiang
authors: Research Institute of Digestive Diseases, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, China.
authors: Deqiang
authors: D
authors: Huang
authors: Research Institute of Digestive Diseases, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, China.
authors: Nonghua
authors: N
authors: Lu
authors: Institute of Basic Medical Sciences, Nanchang University, Nanchang, Jiangxi, 330006, China; Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts, 02118, United States of America.
authors: Zhijun
authors: Z
authors: Luo
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000841:Anisomycin / Q000737:chemistry; D002460:Cell Line; D045744:Cell Line, Tumor; D018076:DNA, Complementary / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000737:chemistry; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D009997:Osmotic Pressure; D018384:Oxidative Stress; D010766:Phosphorylation; D020033:Protein Isoforms / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D013012:Sorbitol / Q000737:chemistry; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11
chemical_list: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D000841:Anisomycin; D018076:DNA, Complementary; D005982:Glutathione Transferase; D006861:Hydrogen Peroxide; D048670:MAP Kinase Kinase 4; D020930:MAP Kinase Kinase Kinases; D020033:Protein Isoforms; D017346:Protein Serine-Threonine Kinases; D013012:Sorbitol; D014409:Tumor Necrosis Factor-alpha; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11; C109790:STK11 protein, human