Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control.
The Hippo pathway plays a key role in organ size control by regulating cell proliferation and apoptosis in Drosophila. Although recent genetic studies have shown that the Hippo pathway is regulated by the NF2 and Fat tumor suppressors, the physiological regulations of this pathway are unknown. Here we show that in mammalian cells, the transcription coactivator YAP (Yes-associated protein), is inhibited by cell density via the Hippo pathway. Phosphorylation by the Lats tumor suppressor kinase leads to cytoplasmic translocation and inactivation of the YAP oncoprotein. Furthermore, attenuation of this phosphorylation of YAP or Yorkie (Yki), the Drosophila homolog of YAP, potentiates their growth-promoting function in vivo. Moreover, YAP overexpression regulates gene expression in a manner opposite to cell density, and is able to overcome cell contact inhibition. Inhibition of YAP function restores contact inhibition in a human cancer cell line bearing deletion of Salvador (Sav), a Hippo pathway component. Interestingly, we observed that YAP protein is elevated and nuclear localized in some human liver and prostate cancers. Our observations demonstrate that YAP plays a key role in the Hippo pathway to control cell proliferation in response to cell contact.
Zhao
Bin
B
Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USA.
Wei
Xiaomu
X
Li
Weiquan
W
Udan
Ryan S
RS
Yang
Qian
Q
Kim
Joungmok
J
Xie
Joe
J
Ikenoue
Tsuneo
T
Yu
Jindan
J
Li
Li
L
Zheng
Pan
P
Ye
Keqiang
K
Chinnaiyan
Arul
A
Halder
Georg
G
Lai
Zhi-Chun
ZC
Guan
Kun-Liang
KL
D048948:14-3-3 Proteins / Q000378:metabolism; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D002450:Cell Communication / Q000235:genetics; D002452:Cell Count; D049109:Cell Proliferation; D002478:Cells, Cultured; D003260:Contact Inhibition / Q000235:genetics*; D004330:Drosophila / Q000235:genetics / Q000254:growth & development; D029721:Drosophila Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008954:Models, Biological; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D011485:Protein Binding; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D021381:Protein Transport; D015398:Signal Transduction / Q000502:physiology; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D000091102:YAP-Signaling Proteins; D000099317:Hippo Kinases
D048948:14-3-3 Proteins; D029721:Drosophila Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D015534:Trans-Activators; D000091102:YAP-Signaling Proteins; C503814:Yki protein, Drosophila; C093503:wts protein, Drosophila; C499474:hpo protein, Drosophila; D000099317:Hippo Kinases