A miR-130a-YAP positive feedback loop promotes organ size and tumorigenesis.
Organ size determination is one of the most intriguing unsolved mysteries in biology. Aberrant activation of the major effector and transcription co-activator YAP in the Hippo pathway causes drastic organ enlargement in development and underlies tumorigenesis in many human cancers. However, how robust YAP activation is achieved during organ size control remains elusive. Here we report that the YAP signaling is sustained through a novel microRNA-dependent positive feedback loop. miR-130a, which is directly induced by YAP, could effectively repress VGLL4, an inhibitor of YAP activity, thereby amplifying the YAP signals. Inhibition of miR-130a reversed liver size enlargement induced by Hippo pathway inactivation and blocked YAP-induced tumorigenesis. Furthermore, the Drosophila Hippo pathway target bantam functionally mimics miR-130a by repressing the VGLL4 homolog SdBP/Tgi. These findings reveal an evolutionarily conserved positive feedback mechanism underlying robustness of the Hippo pathway in size control and tumorigenesis.
Life Sciences Institute and Innovation Center for Cell Signaling Network Hangzhou, Zhejiang 310058, China.|Institute of Biochemistry, College of Life Science Hangzhou, Zhejiang 310058, China.
Shuying
S
Shen
Life Sciences Institute and Innovation Center for Cell Signaling Network Hangzhou, Zhejiang 310058, China.
Xiaocan
X
Guo
Life Sciences Institute and Innovation Center for Cell Signaling Network Hangzhou, Zhejiang 310058, China.
Huan
H
Yan
State Key Laboratory of Cell Biology and Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Yi
Y
Lu
Life Sciences Institute and Innovation Center for Cell Signaling Network Hangzhou, Zhejiang 310058, China.
Xinyan
X
Ji
Institute of Aging Research, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.
Li
L
Li
Department of Hepatobiliary and Pancreatic Surgery and the Key Laboratory of Cancer Prevention and Intervention, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China.
Tingbo
T
Liang
State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
Dawang
D
Zhou
Life Sciences Institute and Innovation Center for Cell Signaling Network Hangzhou, Zhejiang 310058, China.
Xin-Hua
XH
Feng
Department of Medicine, Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Jonathan C
JC
Zhao
Department of Medicine, Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Jindan
J
Yu
Institute of Biochemistry, College of Life Science Hangzhou, Zhejiang 310058, China.
Xing-Guo
XG
Gong
State Key Laboratory of Cell Biology and Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Lei
L
Zhang
Life Sciences Institute and Innovation Center for Cell Signaling Network Hangzhou, Zhejiang 310058, China.
Bin
B
Zhao
D000217:Acyltransferases; D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D063646:Carcinogenesis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D055515:Cysteine-Rich Protein 61 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D004330:Drosophila / Q000378:metabolism; D029721:Drosophila Proteins / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008819:Mice, Nude; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009929:Organ Size / Q000235:genetics; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment; D015398:Signal Transduction; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014183:Transplantation, Heterologous; D000091102:YAP-Signaling Proteins
D048868:Adaptor Proteins, Signal Transducing; C501848:CCN1 protein, human; D055515:Cysteine-Rich Protein 61; D029721:Drosophila Proteins; C554019:MIRN130 microRNA, human; D035683:MicroRNAs; D010750:Phosphoproteins; D014157:Transcription Factors; C488533:VGLL4 protein, human; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D000217:Acyltransferases; C108675:TAFAZZIN protein, human