Energy-dependent regulation of cell structure by AMP-activated protein kinase.
AMP-activated protein kinase (AMPK, also known as SNF1A) has been primarily studied as a metabolic regulator that is activated in response to energy deprivation. Although there is relatively ample information on the biochemical characteristics of AMPK, not enough data exist on the in vivo function of the kinase. Here, using the Drosophila model system, we generated the first animal model with no AMPK activity and discovered physiological functions of the kinase. Surprisingly, AMPK-null mutants were lethal with severe abnormalities in cell polarity and mitosis, similar to those of lkb1-null mutants. Constitutive activation of AMPK restored many of the phenotypes of lkb1-null mutants, suggesting that AMPK mediates the polarity- and mitosis-controlling functions of the LKB1 serine/threonine kinase. Interestingly, the regulatory site of non-muscle myosin regulatory light chain (MRLC; also known as MLC2) was directly phosphorylated by AMPK. Moreover, the phosphomimetic mutant of MRLC rescued the AMPK-null defects in cell polarity and mitosis, suggesting MRLC is a critical downstream target of AMPK. Furthermore, the activation of AMPK by energy deprivation was sufficient to cause dramatic changes in cell shape, inducing complete polarization and brush border formation in the human LS174T cell line, through the phosphorylation of MRLC. Taken together, our results demonstrate that AMPK has highly conserved roles across metazoan species not only in the control of metabolism, but also in the regulation of cellular structures.
Lee
Jun Hee
JH
National Creative Research Initiatives Center for Cell Growth Regulation, Department of Biological Sciences, Korea Advanced Institute of Science and Technology, 373-1 Kusong-Dong, Yusong-Gu, Taejon 305-701, Korea.
Koh
Hyongjong
H
Kim
Myungjin
M
Kim
Yongsung
Y
Lee
Soo Young
SY
Karess
Roger E
RE
Lee
Sang-Hee
SH
Shong
Minho
M
Kim
Jin-Man
JM
Kim
Jaeseob
J
Chung
Jongkyeong
J
D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D000818:Animals; D002460:Cell Line; D016764:Cell Polarity; D029721:Drosophila Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster / Q000166:cytology* / Q000201:enzymology* / Q000235:genetics / Q000254:growth & development; D004734:Energy Metabolism; D005260:Female; D006801:Humans; D008297:Male; D008938:Mitosis; D009097:Multienzyme Complexes / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018994:Myosin Light Chains / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation; D011494:Protein Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D029721:Drosophila Proteins; D009097:Multienzyme Complexes; D018994:Myosin Light Chains; D011494:Protein Kinases; C495775:LKB1 protein, Drosophila; D017346:Protein Serine-Threonine Kinases; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases