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The natural product antroalbol H promotes phosphorylation of liver kinase B1 (LKB1) at threonine 189 and thereby enhances cellular glucose uptake.

ABSTRACT: Hypoglycemic drugs such as metformin increase glucose uptake and utilization by peripheral tissues to maintain glucose homeostasis, and the AMP-activated protein kinase (AMPK) signaling pathway is an important component of this pharmacological activity. Liver kinase B1 (LKB1) acts as a kinase upstream of AMPK and plays an important regulatory role in glucose metabolism. In recent years, as a tumor suppressor, LKB1's antitumor activity has been widely studied, yet its hypoglycemic activity is not clear. Here, using biochemical and cell viability assays, site-directed mutagenesis, immunoblotting, and immunofluorescence staining, we found that a natural product, antroalbol H isolated from the basidiomycete mushroom Antrodiella albocinnamomea, increases cellular glucose uptake in murine L6 myotubes and 3T3-L1 adipocytes. Of note, our results indicated that this effect is related to LKB1-mediated Thr-172 phosphorylation of AMPK?. Furthermore, we observed that antroalbol H induces the phosphorylation of LKB1 specifically at Thr-189 and changes subcellular localization of LKB1. Finally, antroalbol H treatment strikingly promoted glucose transporter type 4 (GLUT4) translocation to the plasma membrane. We conclude that antroalbol H promotes Thr-189 phosphorylation of LKB1, leading to AMPK activation, revealing this residue as a potential target for increasing glucose uptake, and that antroalbol H therefore has potential for managing hyperglycemia.

SUBMITTER: Wang F

PROVIDER: S-EPMC6615669 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Project description:The HOX11/TLX1 (hereafter referred to as HOX11) homeobox gene was originally identified at a t(10;14)(q24;q11) translocation breakpoint, a chromosomal abnormality observed in 5-7% of T cell acute lymphoblastic leukemias (T-ALLs). We previously reported a predisposition to aberrant spindle assembly checkpoint arrest and heightened incidences of chromosome missegregation in HOX11-overexpressing B lymphocytes following exposure to spindle poisons. The purpose of the current study was to evaluate cell cycle specific expression of HOX11.Cell cycle specific expression studies revealed a phosphorylated form of HOX11 detectable only in the mitotic fraction of cells after treatment with inhibitors to arrest cells at different stages of the cell cycle. Mutational analyses revealed phosphorylation on threonine-247 (Thr247), a conserved amino acid that defines the HOX11 gene family and is integral for the association with DNA binding elements. The effect of HOX11 phosphorylation on its ability to modulate expression of the downstream target, cyclin B1, was tested. A HOX11 mutant in which Thr247 was substituted with glutamic acid (HOX11 T247E), thereby mimicking a constitutively phosphorylated HOX11 isoform, was unable to bind the cyclin B1 promoter or enhance levels of the cyclin B1 protein. Expression of the wildtype HOX11 was associated with accelerated progression through the G2/M phase of the cell cycle, impaired synchronization in prometaphase and reduced apoptosis whereas expression of the HOX11 T247E mutant restored cell cycle kinetics, the spindle checkpoint and apoptosis.Our results demonstrate that the transcriptional activity of HOX11 is regulated by phosphorylation of Thr247 in a cell cycle-specific manner and that this phosphorylation modulates the expression of the target gene, cyclin B1. Since it is likely that Thr247 phosphorylation regulates DNA binding activity to multiple HOX11 target sequences, it is conceivable that phosphorylation functions to regulate the expression of HOX11 target genes involved in the control of the mitotic spindle checkpoint.

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The natural product antroalbol H promotes phosphorylation of liver kinase B1 (LKB1) at threonine 189 and thereby enhances cellular glucose uptake.

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