TY - JOUR
T1 - APPL1 mediates adiponectin-induced LKB1 cytosolic localization through the PP2A-PKCζ signaling pathway
AU - Deepa, Sathyaseelan S.
AU - Zhou, Lijun
AU - Ryu, Jiyoon
AU - Wang, Changhua
AU - Mao, Xuming
AU - Li, Cai
AU - Zhang, Ning
AU - Musi, Nicolas
AU - de Fronzo, Ralph A.
AU - Liu, Feng
AU - Dong, Lily Q.
PY - 2011/10/1
Y1 - 2011/10/1
N2 - 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.
AB - 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.
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U2 - 10.1210/me.2011-0082
DO - 10.1210/me.2011-0082
M3 - Article
C2 - 21835890
AN - SCOPUS:80053370831
SN - 0888-8809
VL - 25
SP - 1773
EP - 1784
JO - Molecular Endocrinology
JF - Molecular Endocrinology
IS - 10
ER -