title: APPL1 mediates adiponectin-induced LKB1 cytosolic localization through the PP2A-PKCzeta signaling pathway.
abstract: 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.
authors.affiliation: Department of Cellular and Structural Biology, University of Texas Health Science Centre at San Antonio, San Antonio, Texas 78229-3900, USA.
authors.forename: Sathyaseelan S
authors.initials: SS
authors.lastname: Deepa
authors.forename: Lijun
authors.initials: L
authors.lastname: Zhou
authors.forename: Jiyoon
authors.initials: J
authors.lastname: Ryu
authors.forename: Changhua
authors.initials: C
authors.lastname: Wang
authors.forename: Xuming
authors.initials: X
authors.lastname: Mao
authors.forename: Cai
authors.initials: C
authors.lastname: Li
authors.forename: Ning
authors.initials: N
authors.lastname: Zhang
authors.forename: Nicolas
authors.initials: N
authors.lastname: Musi
authors.forename: Ralph A
authors.initials: RA
authors.lastname: DeFronzo
authors.forename: Feng
authors.initials: F
authors.lastname: Liu
authors.forename: Lily Q
authors.initials: LQ
authors.lastname: Dong
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D052242:Adiponectin / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D003600:Cytosol / Q000187:drug effects / Q000201:enzymology*; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008687:Metformin / Q000494:pharmacology; D051379:Mice; D008954:Models, Biological; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000201:enzymology; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D000099221:Protein Kinase C zeta
chemical_list: D055372:AMP-Activated Protein Kinases; D048868:Adaptor Proteins, Signal Transducing; D052242:Adiponectin; D008687:Metformin; D011493:Protein Kinase C; D054648:Protein Phosphatase 2; D017346:Protein Serine-Threonine Kinases; D012694:Serine; D000099221:Protein Kinase C zeta; C464801:APPL1 protein, human; C491654:Stk11 protein, mouse