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PMID:17974916

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Citation

Zhao, B, Wei, X, Li, W, Udan, RS, Yang, Q, Kim, J, Xie, J, Ikenoue, T, Yu, J, Li, L, Zheng, P, Ye, K, Chinnaiyan, A, Halder, G, Lai, ZC and Guan, KL (2007) Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control. Genes Dev. 21:2747-61

Abstract

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.

Links

PubMed PMC2045129 Online version:10.1101/gad.1602907

Keywords

14-3-3 Proteins/metabolism; Amino Acid Motifs; Amino Acid Sequence; Animals; Cell Communication/genetics; Cell Count; Cell Proliferation; Cells, Cultured; Contact Inhibition/genetics; Drosophila/genetics; Drosophila/growth & development; Drosophila Proteins/antagonists & inhibitors; Drosophila Proteins/chemistry; Drosophila Proteins/metabolism; Drosophila Proteins/physiology; HeLa Cells; Humans; Intracellular Signaling Peptides and Proteins; Mice; Models, Biological; NIH 3T3 Cells; Nuclear Proteins/antagonists & inhibitors; Nuclear Proteins/chemistry; Nuclear Proteins/metabolism; Nuclear Proteins/physiology; Phosphorylation; Protein Binding; Protein Kinases/metabolism; Protein Transport; Protein-Serine-Threonine Kinases/physiology; Signal Transduction/physiology; Trans-Activators/antagonists & inhibitors; Trans-Activators/chemistry; Trans-Activators/metabolism; Trans-Activators/physiology

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:1433B

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P46937

F

Seeded From UniProt

complete

HUMAN:YAP1

located_in

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:YAP1

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:YAP1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P31946

F

Seeded From UniProt

complete

DROME:YAP1

involved_in

GO:0035329: hippo signaling

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:YAP1

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:YAP1

part_of

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:YAP1

involved_in

GO:0008283: cell population proliferation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:YAP1

involved_in

GO:0060242: contact inhibition

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

See also

References

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