ReviewThe YAP and TAZ transcription co-activators: Key downstream effectors of the mammalian Hippo pathway
Highlights
► The Hippo pathway plays a key role in organ size control and dysregulation of the pathway contributes to tumorigenesis. ► The YAP/TAZ transcription co-activators are the major downstream effectors of the Hippo pathway. ► YAP/TAZ are phosphorylated and inhibited by the Lats kinase of the Hippo pathway. ► The TEAD family proteins are the major target transcription factors mediating gene expression by YAP/TAZ.
Section snippets
The Hippo pathway acts to restrict YAP and TAZ in mammals
The Hippo pathway is a newly discovered and evolutionally conserved signaling cascade. It regulates organ size control and stem cell property by governing cell proliferation and apoptosis. In vitro, it is a major regulatory mechanism in cell contact inhibition. Alterations of this pathway are increasingly recognized to be associated with cancer development. Components of the Hippo pathway were firstly discovered by functional genetic screens in Drosophila and shown to be evolutionally and
Identification of YAP and TAZ
YAP was originally identified in chicken as an interacting protein of Yes protein tyrosine kinase. However, the functional significance of this interaction is still not clear. Unlike the use of routine protein-protein interacting approaches, YAP was identified by generating anti-idiotypic antibodies against the N-terminal domain of the Yes protein. The interaction was defined to be mediated by the SH3 domain of Yes and Pro-rich region (PVKQPPPLAP) of YAP. Due to its size of 65 kDa, the chicken
YAP and TAZ as transcriptional co-activators
Although YAP was identified in 1995, its biochemical function remained elusive until a study 4 years later showed that YAP possesses transcriptional co-activator activity [15]. Several transcription factors such as c-Jun, AP-2, NF-E2, C/EBPalpha and PEBP2/CBF, Runx/PEBP2, Krox-20, Krox-24, MEF2B, Oct-4 and p73 contain the PPXY motif and could be potential target for YAP (reviewed in [1]). The PY motif in the transcription factor PEBP2 was investigated and shown to be important for
YAP, TAZ and Yki as downstream targets of the Hippo pathway
Genetic screens in Drosophila have identified Wts, Hpo, Sav and Mats as tumor suppressors regulating tissue growth by controlling cell proliferation and apoptosis. These four proteins are structurally conserved in mammals [17], [18], [19], [20], [21], [22]. Wts–Mats in the fly and LATS1/2–Mob1 in human act as protein kinase complexes downstream of the Hpo/Sav and Mst/Sav, respectively. Yeast two-hybrid screen was performed to identify interacting proteins using the N-terminal region of Wts as
TEAD transcriptional factors as major mediators of YAP, TAZ and Yki in transcription and functional outcome
As briefly mentioned above, YAP was identified as a tight and major interacting protein for TEAD2 and proposed to function as a general transcriptional co-activator for the TEAD transcriptional factors [16]. TEAD1 was originally identified more than 20 years ago as transcriptional enhancer factor 1 (TEF-1) for SV40 virus [39] and it is also involved in transcriptional enhancement of E6 and E7 expression of papillomavirus 16 [40]. There are four related family members (TEAD1–4) in mammals and
Angiomotin family and Wbp2 as novel regulator of YAP and TAZ
Proteomics approach was employed by several labs to identify novel interacting proteins for YAP/TAZ/Yki. In addition to transcription factors and 14-3-3 proteins, there are other proteins co-immunoprecipitated with YAP and TAZ. Among them were Wbp2, Angiomotin (Amot), Angiomotin-like 1 (Amot-L1), and Angiomotin-like 2 (Amot-L2). Wbp2 was earlier identified as an interacting protein for YAP [52], [4], but the functional relevance was not addressed. Two recent studies suggest that Wbp2 is a
The role of YAP and TAZ in cancer development
Increasing evidence supports that YAP and TAZ are oncogenes in mammalian cells [1], [61]. Genome-wide analysis using mouse model of liver cancer showed chromosome amplification at 9qA1, which is syntenic to human chromosome region 11q22. Among genes in the amplified region are YAP and cIAP1, the latter being a dIAP1-related protein. YAP and cIAP1 are individually oncogenic, but they can cooperate to accelerate tumor growth [62]. In an independent study, an amplification of a smaller chromosomal
Conclusions
Rapid progresses in the Hippo pathway studies have established the important function of this signaling pathway in cell proliferation, cell death, organ size control, and tumor development. Convincing genetic and biochemical data have shown that YAP/TAZ are the major downstream effectors of the Hippo pathway directly phosphorylated by Lats though it is likely that Lats may have additional substrates to exert its full biological functions. Moreover, TEADs have emerged as the key transcription
Acknowledgement
We would like to express our sincere thanks to Dr Siew Wee Chan and Alice Tay for their valuable help in preparing this manuscript.
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