Open AccessAPPL1 Mediates Adiponectin-Induced LKB1 Cytosolic Localization Through the PP2A-PKCζ Signaling Pathway
Author(s) -
Sathyaseelan S. Deepa,
Lijun Zhou,
Ji-Yoon Ryu,
Changhua Wang,
Xuming Mao,
Li Cai,
Ning Zhang,
Nicolas Musi,
Ralph A. DeFronzo,
Feng Liu,
Lily Q. Dong
Publication year - 2011
Publication title -
molecular endocrinology
Language(s) - English
Resource type - Journals
eISSN - 1944-9917
pISSN - 0888-8809
DOI - 10.1210/me.2011-0082
Subject(s) - ampk , biology , protein phosphatase 2 , microbiology and biotechnology , dephosphorylation , protein kinase c , pleckstrin homology domain , adiponectin , signal transduction , signal transducing adaptor protein , protein kinase a , phosphorylation , cytosol , leucine zipper , biochemistry , phosphatase , endocrinology , insulin resistance , transcription factor , insulin , enzyme , gene
We recently found that the adaptor protein containing pleckstrin homology domain, phosphotyrosine binding domain and leucine zipper motif (APPL)1 is essential for mediating adiponectin signal to induce liver kinase B (LKB)1 cytosloic translocation, an essential step for activation of AMP-activated protein kinase (AMPK) in cells. However, the underlying molecular mechanisms remain unknown. Here, we demonstrate that treating C2C12 myotubes with adiponectin promoted APPL1 interaction with protein phosphatase 2A (PP2A) and protein kinase Cζ (PKCζ), leading to the activation of PP2A and subsequent dephosphorylation and inactivation of PKCζ. The adiponectin-induced inactivation of PKCζ results in dephosphorylation of LKB1 at Ser(307) and its subsequent translocation to the cytosol, where it stimulates AMPK activity. Interestingly, we found that metformin also induces LKB1 cytosolic translocation, but the stimulation is independent of APPL1 and the PP2A-PKCζ pathway. Together, our study uncovers a new mechanism underlying adiponectin-stimulated AMPK activation in muscle cells and shed light on potential targets for prevention and treatment of insulin resistance and its associated diseases.