AMPK modulates Hippo pathway activity to regulate energy homeostasis.
The Hippo pathway was discovered as a conserved tumour suppressor pathway restricting cell proliferation and apoptosis. However, the upstream signals that regulate the Hippo pathway in the context of organ size control and cancer prevention are largely unknown. Here, we report that glucose, the ubiquitous energy source used for ATP generation, regulates the Hippo pathway downstream effector YAP. We show that both the Hippo pathway and AMP-activated protein kinase (AMPK) were activated during glucose starvation, resulting in phosphorylation of YAP and contributing to its inactivation. We also identified glucose-transporter 3 (GLUT3) as a YAP-regulated gene involved in glucose metabolism. Together, these results demonstrate that glucose-mediated energy homeostasis is an upstream event involved in regulation of the Hippo pathway and, potentially, an oncogenic function of YAP in promoting glycolysis, thereby providing an exciting link between glucose metabolism and the Hippo pathway in tissue maintenance and cancer prevention.
Department of Experimental Radiation Oncology, 1515 Holcombe Boulevard Houston, Texas 77030, USA.
Wenqi
W
Wang
Department of Experimental Radiation Oncology, 1515 Holcombe Boulevard Houston, Texas 77030, USA.
Zhen-Dong
ZD
Xiao
Department of Experimental Radiation Oncology, 1515 Holcombe Boulevard Houston, Texas 77030, USA.
Xu
X
Li
Department of Experimental Radiation Oncology, 1515 Holcombe Boulevard Houston, Texas 77030, USA.
Kathryn E
KE
Aziz
1] Department of Experimental Radiation Oncology, 1515 Holcombe Boulevard Houston, Texas 77030, USA [2] Cancer Biology Program, The University of Texas Graduate School of Biomedical Science, 1515 Holcombe Boulevard Houston, Texas 77030, USA.
Boyi
B
Gan
1] Cancer Biology Program, The University of Texas Graduate School of Biomedical Science, 1515 Holcombe Boulevard Houston, Texas 77030, USA [2] Department of Biochemistry and Molecular Biology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard Houston, Texas 77030, USA.
Randy L
RL
Johnson
1] Department of Experimental Radiation Oncology, 1515 Holcombe Boulevard Houston, Texas 77030, USA [2] Cancer Biology Program, The University of Texas Graduate School of Biomedical Science, 1515 Holcombe Boulevard Houston, Texas 77030, USA.
Junjie
J
Chen
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000378:metabolism; D004734:Energy Metabolism; D004789:Enzyme Activation; D005260:Female; D005947:Glucose / Q000378:metabolism*; D051274:Glucose Transporter Type 3 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D006019:Glycolysis; D057809:HEK293 Cells; D006367:HeLa Cells; D000090683:Hippo Signaling Pathway; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D013217:Starvation; D014158:Transcription, Genetic; D000091102:YAP-Signaling Proteins; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D051274:Glucose Transporter Type 3; D010750:Phosphoproteins; C495689:Slc2a3 protein, mouse; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse; C490501:Lats1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D020741:rho GTP-Binding Proteins; D005947:Glucose