Yin-Yang regulation of adiponectin signaling by APPL isoforms in muscle cells.
APPL1 is a newly identified adiponectin receptor-binding protein that positively mediates adiponectin signaling in cells. Here we report that APPL2, an isoform of APPL1 that forms a dimer with APPL1, can interacts with both AdipoR1 and AdipoR2 and acts as a negative regulator of adiponectin signaling in muscle cells. Overexpression of APPL2 inhibits the interaction between APPL1 and AdipoR1, leading to down-regulation of adiponectin signaling in C2C12 myotubes. In contrast, suppressing APPL2 expression by RNAi significantly enhances adiponectin-stimulated glucose uptake and fatty acid oxidation. In addition to targeting directly to and competing with APPL1 in binding with the adiponectin receptors, APPL2 also suppresses adiponectin and insulin signaling by sequestrating APPL1 from these two pathways. In addition to adiponectin, metformin also induces APPL1-APPL2 dissociation. Taken together, our results reveal that APPL isoforms function as an integrated Yin-Yang regulator of adiponectin signaling and mediate the cross-talk between adiponectin and insulin signaling pathways in muscle cells.
Wang
Changhua
C
Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900, USA.
Xin
Xiaoban
X
Xiang
Ruihua
R
Ramos
Fresnida J
FJ
Liu
Meilian
M
Lee
Hak Joo
HJ
Chen
Hongzhi
H
Mao
Xuming
X
Kikani
Chintan K
CK
Liu
Feng
F
Dong
Lily Q
LQ
D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D052242:Adiponectin / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D005227:Fatty Acids / Q000378:metabolism; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism; D008687:Metformin / Q000494:pharmacology; D051379:Mice; D032446:Myoblasts / Q000187:drug effects* / Q000378:metabolism; D020033:Protein Isoforms; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000494:pharmacology; D011817:Rabbits; D054419:Receptors, Adiponectin / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013347:Subcellular Fractions
D048868:Adaptor Proteins, Signal Transducing; D052242:Adiponectin; C510733:Appl1 protein, mouse; D005227:Fatty Acids; D007004:Hypoglycemic Agents; D007328:Insulin; D020033:Protein Isoforms; D034741:RNA, Small Interfering; D054419:Receptors, Adiponectin; C475419:adiponectin receptor 1, mouse; C475421:adiponectin receptor 2, mouse; D008687:Metformin; D005947:Glucose