Energy stress regulates hippo-YAP signaling involving AMPK-mediated regulation of angiomotin-like 1 protein.
Hippo signaling is a tumor-suppressor pathway involved in organ size control and tumorigenesis through the inhibition of YAP and TAZ. Here, we show that energy stress induces YAP cytoplasmic retention and S127 phosphorylation and inhibits YAP transcriptional activity and YAP-dependent transformation. These effects require the central metabolic sensor AMP-activated protein kinase (AMPK) and the upstream Hippo pathway components Lats1/Lats2 and angiomotin-like 1 (AMOTL1). Furthermore, we show that AMPK directly phosphorylates S793 of AMOTL1. AMPK activation stabilizes and increases AMOTL1 steady-state protein levels, contributing to YAP inhibition. The phosphorylation-deficient S793Ala mutant of AMOTL1 showed a shorter half-life and conferred resistance to energy-stress-induced YAP inhibition. Our findings link energy sensing to the Hippo-YAP pathway and suggest that YAP may integrate spatial (contact inhibition), mechanical, and metabolic signals to control cellular proliferation and survival.
Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
Michael
M
DeRan
Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121, USA.
Jiayi
J
Yang
Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
Che-Hung
CH
Shen
Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121, USA.
Eric C
EC
Peters
Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.
Julien
J
Fitamant
Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
Puiyee
P
Chan
Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121, USA.
Mindy
M
Hsieh
Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
Shunying
S
Zhu
Division of Signal Transduction, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
John M
JM
Asara
Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
Bin
B
Zheng
Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.
Nabeel
N
Bardeesy
Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121, USA.
Jun
J
Liu
Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. Electronic address: xwu@cbrc2.mgh.harvard.edu.
Xu
X
Wu
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000263:Adenylate Kinase / Q000378:metabolism*; D000595:Amino Acid Sequence; D000091082:Angiomotins; D004734:Energy Metabolism; D057809:HEK293 Cells; D000090683:Hippo Signaling Pathway; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D055550:Protein Stability; D015398:Signal Transduction; D013312:Stress, Physiological; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D000091102:YAP-Signaling Proteins
C510063:AMOTL1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D000091082:Angiomotins; D008565:Membrane Proteins; D010750:Phosphoproteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; C092745:LATS1 protein, human; C406449:LATS2 protein, human; D017346:Protein Serine-Threonine Kinases; D000263:Adenylate Kinase