APPL1 mediates adiponectin-induced LKB1 cytosolic localization through the PP2A-PKCζ signaling pathway

Sathyaseelan S. Deepa, Lijun Zhou, Jiyoon Ryu, Changhua Wang, Xuming Mao, Cai Li, Ning Zhang, Nicolas Musi, Ralph A. de Fronzo, Feng Liu, Lily Q. Dong

Research output: Contribution to journalArticle

42 Scopus citations

Abstract

We recently found that the adaptor protein containing pleckstrin homology domain, phosphoty-rosine binding domain and leucine zipper motif (APPL)1 is essential for mediating adiponectin signal to induce liver kinase B (LKB)1 cytosloictranslocation, 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.

Original languageEnglish (US)
Pages (from-to)1773-1784
Number of pages12
JournalMolecular Endocrinology
Volume25
Issue number10
DOIs
StatePublished - Oct 1 2011

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ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

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